Substituted indazole derivatives and related compounds

ABSTRACT

The invention relates to compounds of the formula I                    
     and pharmaceutically acceptable salts thereof, wherein 
     R 2   a  and R 2   b  are independently selected from the group consisting essentially of hydrogen and hereinafter recited substituents, provided that one, but not both of R 2   a  and R 2   b  must be independently selected as hydrogen, wherein said substituents comprise:                    
     wherein the dashed lines in formulas (Ia) and (Ib) independently and optionally represent a single or double bond, provided that in formula (Ia) both dashed lines cannot both represent double bonds at the same time; and 
     R, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 18  and m are as defined. The invention further relates to intermediates for the preparation of the compounds of formula I, and to pharmaceutical compositions containing, and methods of using, the compounds of formula I, or acceptable salts thereof, for the inhibition of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) in a mammal.

This application claims the benefit of Provisional application Ser. No.60/016,861 filed May 3, 1996.

BACKGROUND OF THE INVENTION

This invention relates to a series of novel indazole analogs that areselective inhibitors of phosphodiesterase (PDE) type IV and theproduction of tumor necrosis factor (TNF), and as such are useful in thetreatment of asthma, arthritis, bronchitis, chronic obstructive airwaydisease, psoriasis, allergic rhinitis, dermatitis, and otherinflammatory diseases, AIDS, septic shock and other diseases involvingthe production of TNF. This invention also relates to a method of usingsuch compounds in the treatment of the foregoing diseases in mammals,especially humans, and to pharmaceutical compositions containing suchcompounds.

Since the recognition that cyclic adenosine phosphate (AMP) is anintracellular second messenger, E. W. Sutherland, and T. W. Rall,Pharmacol. Rev., 12, 265, (1960), inhibition of the phosphodiesteraseshas been a target for modulation and, accordingly, therapeuticintervention in a range of disease processes. More recently, distinctclasses of PDE have been recognized, J. A. Beavo et al., TiPS, 11, 150,(1990), and their selective inhibition has led to improved drug therapy,C. D. Nicholson, M. S. Hahid, TiPS, 12, 19, (1991). More particularly,it has been recognized that inhibition of PDE type IV can lead toinhibition of inflammatory mediator release, M. W. Verghese et al., J.Mol. Cell Cardiol., 12 (Suppl. II), S 61, (1989) and airway smoothmuscle relaxation (T. J. Torphy in “Directions for New Anti-AsthmaDrugs,” eds S. R. O'Donnell and C. G. A. Persson, 1988, 37Birkhauser-Verlag). Thus, compounds that inhibit PDE type IV, but whichhave poor activity against other PDE types, would inhibit the release ofinflammatory mediators and relax airway smooth muscle without causingcardiovascular effects or antiplatelet effects.

TNF is recognized to be involved in many infectious and auto-immunediseases, W. Friers, FEBS Letters, 285, 199, (1991). Furthermore, it hasbeen shown that TNF is the prime mediator of the inflammatory responseseen in sepsis and septic shock, C. E. Spooner et al Clinical Immunologyand Immunopathology, 62, S11, (1992).

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula I

and to pharmaceutically acceptable salts thereof, wherein:

R is hydrogen, C₁-C₆ alkyl, —(CH₂)_(n)(C₃-C₇ cycloalkyl) wherein n is 0to 2, (C₁-C₆ alkoxy)C₁-C₆ alkyl, C₂-C₆ alkenyl, —(CH₂)_(n)(C₃-C₉heterocyclyl) wherein n is 0 to 2, or —(Z′)_(b)(Z″)_(c)(C₆-C₁₀ aryl)wherein b and c are independently 0 or 1, Z′ is C₁-C₆ alkylene or C₂-C₆alkenylene, and Z″ is O, S, SO₂, or NR₉, and wherein said alkyl,alkenyl, alkoxyalkyl, heterocyclyl, and aryl moieties of said R groupsare optionally substituted by one or more substituents independentlyselected from halo, hydroxy, C₁-C₅ alkyl, C₂-C₅ alkenyl, C₁-C₅ alkoxy,C₃-C₆ cycloalkoxy, trifluoromethyl, nitro, CO₂-R₉, C(O)NR₉R₁₀, NR₉R₁₀and SO₂NR₉R₁₀;

R₁ is hydrogen, C₁-C₇ alkyl, C₂-C₃ alkenyl, phenyl, C₃-C₇ cycloalkyl, or(C₃-C₇ cycloalkyl)C₁-C₂ alkyl, wherein said alkyl, alkenyl and phenyl R₁groups are optionally substituted with up to 3 substituentsindependently selected from the group consisting of methyl, ethyl,trifluoromethyl, and halo;

R₂ ^(a) and R₂ ^(b) are independently selected from the group consistingessentially of hydrogen and hereinafter recited substituents, providedthat one, but not both of R₂ ^(a) and R₂ ^(b) must be independentlyselected as hydrogen, wherein said substituents comprise:

wherein the dashed lines in formulas (Ia) and (Ib) independently andoptionally represent a single or double bond, provided that in formula(Ia) both dashed lines cannot both represent double bonds at the sametime;

m is 0 to 4;

R₃ is H, halo, cyano, C₂ -C₄ alkynyl optionally mono-substituted byphenyl, pyridyl or pyrimidinyl; C₁-C₄ alkyl optionally substituted byone or more halogens; —CH₂NHC(O)C(O)NH₂, cyclopropyl optionallysubstituted by R₁₁, R₁₇, CH₂OR₉, NR₉R₁₀, CH₂NR₉R₁₀, CO₂R₉, C(O)NR₉R₁₀,C°CR₁₁, C(Z)H or —CH═CR₁₁R₁₁; provided that R₃ is absent when the dashedline in formula (Ia) attached to the ring carbon atom to which R₃ isattached represents a double bond;

R₄ is H, R₆, C(Y)R₁₄, CO₂R₁₄, C(Y)NR₁₇R₁₄, CN, C(NR₁₇)NR₁₇R₁₄,C(NOR₉)R₁₄, C(O)NR₉NR₉C(O)R₉, C(O)NR₉NR₁₇R₁₄, C(NOR₁₄)R₉, C(NR₉)NR₁₇R₁₄,C(NR₁₄)NR₉R₁₀, C(NCN)NR₁₇R₁₄, C(NCN)S(C₁-C₄ alkyl), CR₉R₁₀OR₁₄,CR₉R₁₀SR₁₄, CR₉R₁₀S(O)_(n)R₁₅ wherein n is 0 to 2, CR₉R₁₀NR₁₄R₁₇,CR₉R₁₀NR₁₇SO₂R₁₅, CR₉R₁₀NR₁₇C(Y)R₁₄, CR₉R₁₀NR₁₇CO₂R₁₅,CR₉R₁₀NR₁₇C(Y)NR₁₇R₁₄, CR₉R₁₀NR₁₇C(NCN)NR₁₇R₁₄,CR₉R₁₀NR₁₇C(CR₉NO₂)S(C₁-C₄ alkyl), CR₉R₁₀CO₂R₁₅, CR₉R₁₀C(Y)NR₁₇R₁₄,CR₉R₁₀C(NR₁₇)NR₁₇R₁₄, CR₉R₁₀CN, CR₉R₁₀C(NOR₁₀)R₁₄, CR₉R₁₀C(NOR₁₄)R₁₀,CR₉R₁₀NR₁₇C(NR₁₇)S(C₁-C₄ alkyl), CR₉R₁₀NR₁₇C(NR₁₇)NR₁₇R₁₄,CR₉R₁₀NR₁₇C(O)C(O)NR₁₇R₁₄, CR₉R₁₀NR₁₇O(O)C(O)OR₁₄, tetrazolyl,thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, thiazolidinyl,oxazolyl, oxazolidinyl, triazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl, CR₉R₁₀(tetrazolyl), CR₉R₁₀(thiazolyl), CR₉R₁₀(imidazolyl),CR₉R₁₀(imidazolidinyl), CR₉R₁₀(pyrazolyl), CR₉R₁₀(thiazolidinyl),CR₉R₁₀(oxazolyl), CR₉R₁₀(oxazolidinyl), CR₉R₁₀(triazolyl),CR₉R₁₀(isoxazolyl), CR₉R₁₀(oxadiazolyl), CR₉R₁₀(thiadiazolyl),CR₉R₁₀(morpholinyl), CR₉R₁₀(piperidinyl), CR₉R₁₀(piperazinyl), orCR₉R₁₀(pyrrolyl), wherein said heterocyclic groups and moieties for saidR₄ substituents are optionally substituted by one or more R₁₄substituents;

R₅ is R₉, OR₉, —CH₂OR₉, cyano, C(O)R₉, CO₂R₉, C(O)NR₉R₁₀, or NR₉R₁₀,provided that R₅ is absent when the dashed line in formula (Ia)represents a double bond;

or R₄ and R₅ are taken together to form ═O or ═R₈;

or R₅ is hydrogen and R₄ is OR₁₄, SR₁₄, S(O)_(n)R₁₅ wherein n is 0 to 2,SO₂NR₁₇R₁₄, NR₁₇R₁₄, NR₁₄C(O)R₉, NR₁₇C(Y)R₁₄, NR₁₇C(O)OR₁₅,NR₁₇C(Y)NR₁₇R₁₄, NR₁₇SO₂NR₁₇R₁₄, NR₁₇C(NCN)NR₁₇R₁₄, NR₁₇SO₂R₁₅,NR₁₇C(CR₉NO₂)NR₁₇R₁₄, NR₁₇C(NCN)S(C₁-C₄ alkyl), NR₁₇C(CR₉NO₂)S(C₁-C₄alkyl), NR₁₇C(NR₁₇)NR₁₇R₁₄, NR₁₇C(O)C(O)NR₁₇R₁₄, or NR₁₇C(O)C(O)OR₁₄;

R₆ is independently selected from methyl and ethyl optionallysubstituted by one or more halogens;

R₇ is OR₁₄, SR₁₄, SO₂NR₁₇R₁₄, NR₁₇R₁₄, NR₁₄C(O)R₉, NR₁₇C(Y)R₁₄,NR₁₇C(O)OR₁₅, S(O)_(n)R₁₂ wherein n is 0 to 2, OS(O)₂R₁₂, OR₁₂,OC(O)NR₁₃R₁₂, OC(O)R₁₃, OCO₂R₁₃, O(CR₁₂R₁₃)_(m)OR₁₂ wherein m is 0 to 2,CR₉R₁₀OR₁₄, CR₉R₁₀NR₁₇R₁₄, C(Y)R₁₄, CO₂R₁₄, C(Y)NR₁₇R₁₄, CN,C(NR₁₇)NR₁₇R₁₄, C(NOR₉)R₁₄, C(O)NR₉NR₉C(O)R₉, C(O)NR₉NR₁₇R₁₄,C(NOR₁₄)R₉, C(NR₉)NR₁₇R₁₄, C(NR₁₄)NR₉R₁₀, C(NCN)NR₁₇R₁₄, C(NCN)S(C₁-C₄alkyl), tetrazolyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl,thiazolidinyl, oxazolyl, oxazolidinyl, triazolyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, wherein said heterocyclic groups areoptionally substituted by one or more R₁₄ substituents;

R₈ is —NR₁₅, —NCR₉R₁₀(C₂-C₆ alkenyl), —NOR₁₄, —NOR₁₉, —NOCR₉R₁₀(C₂-C₆alkenyl), —NNR₉R₁₄, —NNR₉R₁₉, —NCN, —NNR₉C(Y)NR₉R₁₄, —C(CN)₂, —CR₁₄CN,—CR₁₄CO₂R₉, —CR₁₄C(O)NR₉R₁₄, —C(CN)NO₂, —C(CN)CO₂(C₁-C₄ alkyl),—C(CN)OCO₂(C₁-C₄ alkyl), —C(CN)(C₁-C₄ alkyl), —C(CN)C(O)NR₉R₁₄,2-(1,3-dithiane), 2-(1,3-dithiolane), dimethylthio ketal, diethylthioketal, 2-(1,3-dioxolane), 2-(1,3-dioxane), 2-(1,3-oxathiolane), dimethylketal or diethyl ketal;

R₉ and R₁₀ are independently hydrogen or C₁-C₄ alkyl optionallysubstituted by up to three fluorines;

R₁₁ is independently fluoro or R₁₀;

R₁₂ is C₁-C₆ alkyl, C₂-C₃ alkenyl, C₃-C₇ cycloalkyl, (C₃-C₇cycloalkyl)C₁-C₂ alkyl, C₅-C₁₀ aryl, or C₃-C₉ heterocyclyl, wherein saidR₁₂ groups are optionally substituted with up to 3 substituentsindependently selected from the group consisting of methyl, ethyl,trifluoromethyl, and halo;

R₁₃ is hydrogen or R₁₂;

R₁₄ is hydrogen or R₁₅, or when R₁₄ and R₁₇ are as NR₁₇R₁₄ then R₁₇ andR₁₄ can be taken together with the nitrogen to form a 5 to 7 memberedring optionally containing at least one additional heteroatom selectedfrom O, N and S;

R₁₅ is C₁-C₆ alkyl or —(CR₉R₁₀)_(n)R₁₆ wherein n is 0 to 2 and R₁₆ andsaid C₁-C₆ alkyl are optionally substituted by one or more substituentsindependently selected from halo, nitro, cyano, NR₁₀R₁₇, C(O)R₉, OR₉,C(O)NR₁₀R₁₇, OC(O)NR₁₀R₁₇, NR₁₇C(O)NR₁₇R₁₀, NR₁₇C(O)R₁₀, NR₁₇C(O)O(C₁-C₄alkyl), C(NR₁₇)NR₁₇R₁₀, C(NCN)NR₁₇R₁₀, C(NCN)S(C₁-C₄ alkyl),NR₁₇C(NCN)S(C₁-C₄ alkyl), NR₁₇C(NCN)NR₁₇R₁₀, NR₁₇SO₂(C₁-C₄ alkyl),S(O)_(n)(C₁-C₄ alkyl) wherein n is 0 to 2, NR₁₇C(O)C(O)NR₁₇R₁₀,NR₁₇C(O)C(O)R₁₇, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl,tetrazolyl, or C₁-C₂ alkyl optionally substituted with one to threefluorines;

R₁₆ is C₃-C₇ cycloalkyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl,triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl,thienyl, thiazolyl, quinolinyl, naphthyl, or phenyl;

R₁₇ is OR₉ or R₁₀;

R₁₈ is H, C(Y)R₁₄, CO₂R₁₄, C(Y)NR₁₇R₁₄, CN, C(NR₁₇)NR₁₇R₁₄, C(NOR₉)R₁₄,C(O)NR₉NR₉C(O)R₉, C(O)NR₉NR₁₇R₁₄, C(NOR₁₄)R₉, C(NR₉)NR₁₇R₁₄,C(NR₁₄)NR₉R₁₀, C(NCN)NR₁₇R₁₄, C(NCN)S(C₁-C₄ alkyl), CR₉R₁₀OR₁₄,CR₉R₁₀SR₁₄, CR₉R₁₀S(O)_(n)R₁₅ wherein n is 0 to 2, CR₉R₁₀NR₁₄R₁₇,CR₉R₁₀NR₁₇SO₂R₁₅, CR₉R₁₀NR₁₇C(Y)R₁₄, CR₉R₁₀NR₁₇CO₂R₁₅,CR₉R₁₀NR₁₇C(Y)NR₁₇R₁₄, CR₉R₁₀NR₁₇C(NCN)NR₁₇R₁₄,CR₉R₁₀NR₁₇C(CR₉NO₂)S(C₁-C₄ alkyl), tetrazolyl, thiazolyl, imidazolyl,imidazolidinyl, pyrazolyl, thiazolidinyl, oxazolyl, oxazolidinyl,triazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, wherein saidheterocyclic groups are optionally substituted by one or more R₁₄substituents;

R₁₉ is —C(O)R₁₄, —C(O)NR₉R₁₄, —S(O)₂R₁₅, or —S(O)₂NR₉R₁₄;

Y is O or S; and,

Z is O, NR₁₇, NCN, C(—CN)₂, CR₉CN, CR₉NO₂, CR₉CO₂R₉, CR₉C(O)NR₉R₁₀,C(—CN)CO₂(C₁-C₄ alkyl) or C(—CN)C(O)NR₉R₁₀.

R₂ ^(a) and R₂ ^(b) are defined hereinabove as being a memberindependently selected from the group consisting essentially of hydrogenand thereafter recited substituents, provided that one, but not both ofR₂ ^(a) and R₂ ^(b) must be independently selected as hydrogen. Thus,only one of R₂ ^(a) or R₂ ^(b) is present, and they both have the samedefinition. As such, they define the stereoisomers of the compounds offormula I, i.e., for any given compound of formula I, one stereoisomerwill be defined by R₂ ^(a) while the other stereoisomer will be definedby R₂ ^(b). Both groups of stereoisomers are contemplated to have thesame type of biological activity, i.e., PDE4 inhibition, and aretherefore considered to be useful in the same methods of therapeutictreatment as herein described. There may be some difference in the levelof biological activity resulting from the variations in conformationpresented to the receptor(s) involved by each group of stereoisomers, orby differences in the pharmacodynamics of the stereoisomers. However,such differences in the degree of activity, rather than in the kind ofactivity present, permit the conclusion that a single invention isinvolved.

The invention also relates to compounds of formulas X, XVI, and XIX,which are intermediates that are useful in the preparation of compoundsof formula I:

wherein R and R₁ are defined as indicated above for the compound offormula I.

The term “halo”, as used herein, unless otherwise indicated, meansfluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloroand bromo.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight or branchedmoieties.

The term “alkoxy”, as used herein, unless otherwise indicated, includesO-alkyl groups wherein “alkyl” is defined above.

The term “alkenyl”, as used herein, unless otherwise indicated, includesunsaturated alkyl groups having one or more double bonds wherein “alkyl”is defined above.

The term “cycloalkyl”, as used herein, unless otherwise indicated,includes saturated monovalent cyclo hydrocarbon radicals includingcyclobutyl, cyclopentyl and cycloheptyl.

The term “aryl”, as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl.

The term “heterocyclyl”, as used herein, unless otherwise indicated,includes aromatic and non-aromatic heterocyclic groups containing one ormore heteroatoms each selected from O, S and N. The heterocyclic groupsinclude benzo-fused ring systems and ring systems substituted with anoxo moiety. With reference to the R₄ substituent of formula Ia, theC₃-C₉ heterocyclic group can be attached to the C₁-C₆ alkyl group by anitrogen or, preferably, a carbon atom. An example of a C₃ heterocyclicgroup is thiazolyl, and an example of a C₉ heterocyclic group isquinolinyl. Examples of non-aromatic heterocyclic groups arepyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl,pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,thienyl, isoxazolyl and thiazolyl. Heterocyclic groups having a fusedbenzene ring include benzimidazolyl.

Where heterocyclic groups are specifically recited or covered assubstituents for the compound of formula I, it is understood that allsuitable isomers of such heterocyclic groups are intended. Thus, forexample, in the definition of the substituent R₄, the term “thiazolyl”includes 2-, 4- or 5-thiazolyl; the term “imidazolyl” includes 2-, 4- or5-imidazolyl; the term “pyrazolyl” includes 3-, 4- or 5-pyrazolyl; theterm “oxazolyl” includes 2-, 4- or 5-oxazolyl; the term “isoxazolyl”includes 3-, 4- or 5-isoxazolyl, and so on. Likewise, in the definitionof substituent R₁₆, the term “pyridyl” includes 2-, 3- or 4-pyridyl.

Preferred compounds of formula I include those wherein R₂ is a group ofthe formula (Ia) wherein R₃ and R₅ are cis as follows:

Other preferred compounds of formula I include those wherein R₂ is agroup of the formula (Ia) wherein the dashed line attached to the ringcarbon atom to which R₃ is attached represents a single bond and R₃ andR₄ are cis.

Other preferred compounds of formula I include those wherein R iscyclohexyl, cyclopentyl, cyclobutyl, methylenecyclopropyl, isopropyl,phenyl or 4-fluoro-phenyl.

Other preferred compounds of formula I include those wherein R₁ is C₁-C₂alkyl optionally substituted by up to three fluorines, and, morepreferably, those wherein R₁ is ethyl.

Other preferred compounds of formula I include those wherein R₂ is agroup of formula (Ia) wherein the dashed line attached to the ringcarbon atom to which R₃ is attached represents a single bond.

Other preferred compounds of formula I include those wherein R₂ is agroup of formula (Ia) wherein the dashed line attached to the ringcarbon atom to which R₃ is attached represents a single bond and R₃ iscyano.

Other preferred compounds of formula I include those wherein R₂ is agroup of formula (Ia) wherein the dashed line attached to the ringcarbon atom to which R₃ is attached represents a single bond, m is 0 andR₅ is hydrogen.

Other preferred compounds of formula I include those wherein R₂ is agroup of formula (Ia) wherein the dashed line attached to the ringcarbon atom to which R₃ is attached represents a single bond, m is 0, R₅is hydrogen and R₄ is —OH, —CH₂OH, —C(CH₃)₂OH, —CO₂H, —CO₂CH₃,—CO₂CH₂CH₃, or —CH₂C(O)NH₂.

Other more preferred compounds of formula I include those wherein R iscyclobutyl, cyclopentyl, cyclohexyl, or 4-fluoro-phenyl; R₁ is ethyl; R₂is a group of formula (Ia) wherein the dashed line attached to the ringcarbon atom to which R₃ is attached represents a single bond, R₃ iscyano, m is 0, R₅ is hydrogen, and R₄ is —CO₂H.

Preferred compounds of formulas X, XVI, and XIX include those wherein R₁is ethyl.

Other preferred compounds of formulas X and XIX include those wherein Ris cyclohexyl, cyclopentyl, methylenecyclopropyl, isopropyl, phenyl or4-fluoro-phenyl.

Specific preferred compounds include:

1-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-oxocyclohexanecarbonitrile;

Trans-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid methylester;

Cis-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid methyl ester;

Trans-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid;

Cis-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid;

1-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-oxocyclohexanecarbonitrile;

Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid methyl ester;

Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid methyl ester;

Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid;

Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid;

Cis-1-(1-cyclohexyl-3-ethyl-1H-indazole-6-yl)-4-hydroxymethylcyclohexanecarbonitrile;

Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid amide;

Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid amide;

Cis-1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-(1-hydroxy-1-methylethyl)cyclohexanecarbonitrile;

Cis-1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;

Cis-1-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]-4-hydroxycyclohexanecarbonitrile;

Cis-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;

Cis-1-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;

Cis-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-4-methylcyclohexanecarbonitrile;

Trans-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-4-methylcyclohexanecarbonitrile;

Cis-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid;

Trans-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid;

6-Bromo-3-ethyl-1-(4-fluorophenyl)-1H-indazole;

4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]-4-hydroxycyclohexanecarboxylicacid ethyl ester;

4-Cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohexanecarboxylicacid ethyl ester;

4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylicacid ethyl ester;

4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid ethyl ester;

Cis-4-Cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohexanecarboxylicacid;

4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylicacid; and

4-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarboxylicacid.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups which maybe present in the compounds of formula I. For example, pharmaceuticallyacceptable salts include sodium, calcium and potassium salts ofcarboxylic acid groups and hydrochloride salts of amino groups. Otherpharmaceutically acceptable salts of amino groups are hydrobromide,sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, citrate, tartrate, lactate, mandelate,methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.

Certain compounds of formula I may have asymmetric centers and thereforeexist in different enantiomeric forms. All optical isomers andstereoisomers of the compounds of formula I, and mixtures thereof, areconsidered to be within the scope of the invention. With respect to thecompounds of formula I, the invention includes the use of a racemate, asingle enantiomeric form, a single diastereomeric form, or mixturesthereof. The compounds of formula I may also exist as tautomers. Thisinvention relates to the use of all such tautomers and mixtures thereof.

The present invention further relates to a pharmaceutical compositionfor the inhibition of phosphodiesterase (PDE) type IV or the productionof tumor necrosis factor (TNF) in a mammal comprising a pharmaceuticallyeffective amount of a compound according to formula I, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present invention further relates to a method for the inhibition ofphosphodiesterase (PDE) type IV or the production of tumor necrosisfactor (TNF) by administering to a patient an effective amount of acompound according to formula I or a pharmaceutically acceptable saltthereof.

The present invention further relates to a pharmaceutical compositionfor the prevention or treatment of asthma, joint inflammation,rheumatoid arthritis, gouty arthritis, rheumatoid spondylitis,osteoarthritis, and other arthritic conditions; sepsis, septic shock,endotoxic shock, gram negative sepsis, toxic shock syndrome, acuterespiratory distress syndrome, cerebal malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoidosis, bone resorptiondiseases, reperfusion injury, graft vs. host reaction, allograftrejections, fever and myalgias due to infection (e.g. bacterial, viralor fungal infection) such as influenza, cachexia secondary to infectionor malignancy, cachexia secondary to human acquired immune deficiencysyndrome (AIDS), AIDS, HIV, ARC (AIDS related complex), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,pyresis, multiple sclerosis, type 1 diabetes mellitus, autoimmunediabetes, systemic lupus erythematosis, bronchitis, chronic obstructiveairway disease, psoriasis, Bechet's disease, anaphylactoid purpuranephritis, chronic glomerulonephritis, inflammatory bowel disease,leukemia, allergic rhinitis, or dermatitis, in a mammal, comprising apharmaceutically effective amount of a compound according to formula I,or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier.

This invention further relates to a method of treating or preventing theforegoing specific diseases and conditions by administering to a patientan effective amount of a compound according to formula I or apharmaceutically acceptable salt thereof.

Certain “aminal” or “acetal”-like chemical structures within the scopeof formula I may be unstable. Such structures may occur where twoheteroatoms are attached to the same carbon atom. For example, where Ris C₁-C₆ alkyl substituted by hydroxy, it is possible that the hydroxymay be attached to the same carbon that is attached to the nitrogen atomfrom which R extends. It is to be understood that such unstablecompounds are not within the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction schemes 1-4 illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated, R and R¹in the reaction schemes are defined as above.

The preparation of compounds of formula I can be carried out by oneskilled in the art according to one or more of the synthetic methodsoutlined in schemes 1-4 above and the examples referred to below. Instep 1 of scheme 1, the carboxylic acid of formula II, which isavailable from known commercial sources or can be prepared according tomethods known to those skilled in the art, is nitrated under standardconditions of nitration (HNO₃/H₂SO₄, 0° C.) and the resulting nitroderivative of formula III is hydrogenated in step 2 of scheme 1 usingstandard hydrogenation methods (H₂-Pd/C under pressure) at ambienttemperature (20-25° C.) for several hours (2-10 hours) to provide thecompound of formula IV. In step 3 of scheme 1, the amino benzoic acid offormula IV is reacted with a base such as sodium carbonate under aqueousconditions and gently heated until mostly dissolved. The reactionmixture is chilled to a lower temperature (about 0° C.) and treated withsodium nitrate in water. After about 15 minutes, the reaction mixture isslowly transferred to an appropriate container holding crushed ice and astrong acid such as hydrochloric acid. The reaction mixture is stirredfor 10-20 minutes and then added, at ambient temperature, to a solutionof excess t-butyl thiol in an aprotic solvent such as ethanol. Thereaction mixture is acidified to a pH of 4-5 through addition of aninorganic base, preferably saturated aqueous Na₂CO₃, and the reactionmixture is allowed to stir at ambient temperature for 1-3 hours.Addition of brine to the reaction mixture, followed by filtration,provides the sulfide of formula V.

In step 4 of scheme 1, the sulfide of formula V is converted to thecorresponding indazole carboxylic acid of formula VI by reacting thesulfide of formula V with a strong base, preferably potassiumt-butoxide, in dimethyl sulfoxide (DMSO) at ambient temperature. Afterstirring for several hours (1-4 hours), the reaction mixture isacidified with a strong acid, such as hydrochloric or sulfuric acid, andthen extracted using conventional methods. In step 5 of scheme 1, theindazole carboxylic acid of formula VI is converted to the correspondingester of formula VII by conventional methods known to those skilled inthe art. In step 6 of scheme 1, the compound of formula VIII is providedthrough alkylation of the ester of formula VII by subjecting the esterto conventional alkylation conditions (strong baselvarious alkylatingagents and, optionally, a copper catalyst such as CuBr₂) in a polaraprotic solvent, such as tetrahydrofuran (THF), N-methylpyrrolidinone ordimethylformamide (DMF), at ambient or higher temperature (25-200° C.)for about 6-24 hrs, preferably about 12 hours. In step 7 of scheme 1,the compound of formula VIII is converted to the corresponding alcoholof formula IX by following conventional methods known to those skilledin the art for reducing esters to alcohols. Preferably, the reduction iseffected through use of a metal hydride reducing agent, such as lithiumaluminum hydride, in a polar aproptic solvent at a low temperature(about 0° C.). In step 8 of scheme 1, the alcohol of formula IX isoxidized to the corresponding aldehyde of formula X according toconventional methods known to those skilled in the art. For example, theoxidation can be effected through use of a catalytic amount oftetrapropylammonium perrutenate and excess N-methylmorpholine-N-oxide,as described in J. Chem. Soc., Chem. Commun., 1625 (1987), in ananhydrous solvent, preferably methylene chloride.

Scheme 2 provides an alternative method of preparing the aldehyde offormula X. In step 1 of scheme 2, the compound of formula XI is nitratedusing conventional nitration conditions (nitric and sulfuric acid) toprovide the compound of formula XII. In step 2 of scheme 2, the nitroderivative of formula XII is reduced to the corresponding amine offormula XIII according to conventional methods known to those skilled inthe art. Preferably, the compound of formula XII is reduced to the amineof formula XIII using anhydrous stannous chloride in an anhydrousaprotic solvent such as ethanol. In step 3 of scheme 2, the amine offormula XII is converted to the corresponding indazole of formula XIV bypreparing the corresponding diazonium fluoroforates as described in A.Roe, Organic Reactions, Vol. 5, Wiley, New York, 1949, pp. 198-206,followed by phase transfer catalyzed cyclization as described in R. A.Bartsch and I. W. Yang, J. Het. Chem. 21, 1063 (1984). In step 4 ofscheme 2, alkylation of the compound of formula XIV is performed usingstandard methods known to those skilled in the art (i.e. strong base,polar aprotic solvent and an alkyl halide) to provide the N-alkylatedcompound of formula XV. In step 5 of scheme 2, the compound of formulaXV is subjected to metal halogen exchange employing an alkyl lithium,such as n-butyl lithium, in a polar aprotic solvent, such as THF, at lowtemperature (−50° C. to 100° C. (−78° C. preferred)) followed byquenching with DMF at low temperature and warming to ambient temperatureto provide the aldehyde compound of formula X.

Scheme 3 illustrates the preparation of a compound of formula XXII whichis a compound of formula I wherein R₂ is a ring moiety of formula (Ia).In step 1 of scheme 3, the aldehyde moiety of the compound of formula Xis converted to an appropriate leaving group, such as a halogen,mesylate or another leaving group familiar to those skilled in the art,followed by reacting the resulting compound with sodium cyanate in apolar solvent such as DMF to provide the compound of formula XVI. Instep 2 of scheme 3, the compound of formula XVI is reacted under basicconditions with methyl acrylate (or related derivatives depending on theR₂ group to be added) in an aprotic solvent such as ethylene glycoldimethyl ether (DME) at high temperature, preferably at reflux, toprovide the compound of formula XVII. In step 3 of scheme 3, thecompound of formula XVII is converted to the compound of formula XVIIIusing a strong base, such as sodium hydride, and a polar aproticsolvent, such as DMF or THF, at elevated temperature, preferably atreflux.

In step 4 of scheme 3, the compound of formula XVIII is decarboxylatedusing conventional methods, such as using sodium chloride in DMSO at atemperature of about 140° C., to provide the compound of formula XIX. Instep 5 of scheme 3, derivatization of the compound of formula XIX to thecorresponding dithian-2-ylidine cyclohexane carbonitrile of formula XXis done by reaction with 2-lithio-1,3-dithiane. In step 5-a of scheme 3,further derivatization of the compound of formula XIX to thecorresponding cyclohexane carbonitrile of formula XXV which ispara-substituted on the cyclohexane group with an hydroxyl moiety and anR₄ substituent, e.g., methyl, is carried out by reacting the ketone witha nucleophilic reagent, e.g., an alkyl lithium compound or a Grignardreagent in accordance with procedures well known in the art. In step 5-bof scheme 3, further derivatization of the compound of formula XIX tothe corresponding cyclohexane carbonitrile of formula XXVI which ispara-substituted on the cyclohexane group with an hydroxyl moiety, iscarried out by reducing the ketone with, e.g., lithium aluminum hydrideor sodium borohydride in accordance with procedures well known in theart. In step 6 of scheme 3, the compound of formula XX is converted tothe corresponding ester of formula XXI using mercury (II) chloride andperchloric acid in a polar aprotic solvent such as methanol. In step 7of scheme 3, the compound of formula XXI is converted through hydrolysisto the corresponding carboxylic acid of formula XXII using a standardmethod of hydrolysis, such as using aqueous sodium hydroxide in a polarsolvent, or any of numerous existing hydrolysis methods known to thoseskilled in art as described in T. Green and P. G. M. Wets, ProtectingGroups in Organic Synthesis, 2nd Edition (John Wiley and Sons, New York(1991)). The synthetic steps described for scheme 3 are analogous to thesynthetic methods provided for the preparation of correspondingcatechol-containing compounds in PCT published applications WO 93/19751and WO 93/17949.

Other compounds of formula I wherein R₂ is selected from moieties (Ia),(Ib), (Ic) and (Id), can be prepared from one or more of theintermediate compounds described in schemes I-III. In particular, thealdehyde of formula X or the keto compound of formula XIX can be used toprepare various compounds of formula I. Any of the various R₂ moietiesof formulas (Ia), (Ib), (Ic) or (Id) can be introduced into one or moreof the intermediate compounds referred to above using synthetic methodsprovided for corresponding non-indazole analogs in PCT publishedapplications WO 93/19748, WO 93/19749, WO 93/09751, WO 93/19720, WO93/19750, WO 95/03794, WO 95/09623, WO 95/09624, WO 95/09627, WO95/09836, and WO 95/09837. For example, with reference to step 1 ofscheme 4, the carboxylic acid of formula XXII can be converted to thealcohol of formula XXIII by reduction with various metal hydrides in apolar solvent as described in Example 9, referred to below, and inaccordance with synthetic methods provided for correspondingnon-indazole analogs in PCT published applications publication numbersWO 93/19747, WO 93/19749 and WO 95109836. Further, with reference tostep 2 of scheme 4, the carboxylic acid of formula XXII can be convertedto the corresponding carboxamide of formula XXIV through conversion toan intermediate acid chloride using conventional synthetic methods, andthen reacting the acid chloride with ammonia in an aprotic solvent.Other carboxamide analogs of formula XXIV can be prepared throughreaction of the acid chloride intermediate with various primary orsecondary amines according to conventional methods known to thoseskilled in the art and as described in the PCT published applicationsreferred to above.

Other compounds of formula I can be prepared from the intermediatecompound of formula XIX in accord with synthetic methods provided forcorresponding non-indazole analogs in the PCT published applicationsreferred to above. Compounds of formula I wherein R₂ is a moiety offormula (Ia), and either R₄ or R₅ is H, can be prepared from the ketointermediate of formula XIX by reaction with a base such as lithiumdiisopropylamine in a polar aprotic solvent, such as THF, and excessN-phenyltrifluoromethylsulfonamide as described in POT publishedapplication WO 93/19749 for corresponding non-indazole analogs.Compounds of formula I wherein R₂ is a moiety of formula Ia, R₄ ishydrogen, and R₅ is —CO₂CH₃ or —CO₂H, can be prepared from the ketointermediate of formula XIX through reaction with triflic anhydride inthe presence of a tertiary amine base followed by reaction of theresulting triflate with (triphenylphosphine)palladium and carbonmonoxide in the presence of an alcohol or amine to provide the methylester compounds of formula I wherein R₅ is —CO₂CH₃. The methyl estercompound can be hydrolyzed to obtain the corresponding carboxylic acidcompound by employing standard methods for hydrolysis such as sodium orpotassium hydroxide in aqueous methanol/tetrahydrofuran. Such syntheticmethods are further described in PCT published application WO 93/19749for corresponding non-indazole analogs.

Other compounds of formula I can be prepared from the intermediatecompound of formula XIX in accord with synthetic methods described forcorresponding non-indazole analogs in the published PCT applicationsreferred to above. Compounds of formula I wherein R₂ is a moiety offormula (Ia), R₅ is hydrogen, and R₄ is hydroxy, can be prepared throughreaction of the intermediate of formula XIX with an appropriate reducingagent such as lithium borohydride, diamyl borane, lithium aluminumtris(t-butoxide), or sodium borohydride in a suitable non-reactingsolvent such as 1,2-dimethoxy ethane, THF or alcohol. Compounds offormula I wherein R₂ is a moiety of formula (Ia), R₅ is hydrogen and R₄is —NH₂, —NHCH₃, or —N(CH₃)₂, can be prepared by reacting theintermediate of formula XIX with an ammonium salt, such as ammoniumformate, methylamine hydrochloride or dimethylamine hydrochloride, inthe presence of sodium cyanoborohydride in an appropriate solvent suchas alcohol.

Alternatively, compounds of formula I wherein R₂ is a moiety of formulaIa, R₄ amino, and R₅ is hydrogen, can be prepared by reacting thecorresponding alcohol of formula I (R₄=OH, R₅=H) with a complex of anazadicarboxylate ester in the presence of an imide or phthalimidefollowed by reaction in an alcoholic solvent such as ethanol. Compoundsof formula I wherein R₂ is a moiety of formula (Ia), R₅ is H, and R₄ is—SR₁₄ can be prepared by reacting the corresponding compound wherein R₄is a leaving group such as mesylate, tosylate, bromine or chlorine, witha metal salt of mercaptan such as NaSR₁₄ in an appropriate aproticsolvent. Corresponding compounds of formula I wherein R₄ is —SH can beprepared by reacting the corresponding alcohol (R₄=OH) with a complex ofa phosphine, such as triphenyl phosphine, and an azidocarboxylate esterin the presence of thiolacetic acid followed by hydrolysis of theresulting thiolacetate. Furthermore compounds of this structure whereinR₄ is hydroxy can be interconverted using a standard alcohol inversionprocedure known to those skilled in the art. The foregoing compounds offormula I wherein R₂ is a moiety of formula (Ia), R₅ is hydrogen, and R₄is hydroxy, —SH or —NH₂, can be converted to various other compounds offormula I through one or more synthetic methods described in PCTpublished applications WO 93/19751 and WO 93/19749 for correspondingnon-indazole analogs.

Compounds of formula I wherein R₂ is a moiety of formula (Ia) and thedashed line represents a double bond attached to the ring carbon atom towhich substituent R₃ is attached, can be prepared from the intermediateof formula XIX by following one or more synthetic methods provided forthe preparation of corresponding non-indazole analogs in PCT publishedapplication WO 93/19720. Compounds of formula I wherein R₂ is a moietyof formula (Ia), and R₄ and R₅ are taken together to form =O or =R₈,wherein R₈ is as defined above, can be prepared from the correspondingketone intermediate of formula XIX following one or more syntheticmethods provided for corresponding non-indazole analogs in PCT publishedapplication WO 93/19750. Other compounds of formula I wherein R₂ is amoiety of formula (Ia) and R₄ and R₅ are taken together as =R₈ can beprepared from the intermediate of formula XIX following one or moresynthetic methods provided for the preparation of correspondingnon-indazole analogs in PCT published application WO 93/19748.

Compounds of formula I wherein R₂ is a moiety of formula (Ib) can beprepared from one or more of the intermediates referred to above, suchas the bromoindazole intermediate of formula XV, following one or moresynthetic methods provided for the preparation of correspondingnon-indazole analogs in PCT published applications WO 95/09627, WO95/09624, WO 95/09623, WO 95/09836 and WO 95/03794. Compounds of formulaI wherein R₂ is a moiety of formula (Ic) can be prepared from theintermediate of formula XV following one or more of synthetic methodsprovided for the preparation of corresponding non-indazole analogs inPCT published applications WO 95/09624 and WO 95/09837. Compounds offormula I wherein R₂ is a moiety of formula (Id) can be prepared fromthe bromoindazole intermediate of formula XV employing one or moresynthetic methods provided for the preparation of the correspondingcatechol-containing analogs in PCT published applications WO 95109627,WO 95/09623 and WO 95/09624.

Particularly preferred compounds of the present invention are thoserepresented by the following formulas:

A method for the preparation of the second of the above-depictedcompounds is described in further below-recited Example 23. It is alsopossible to prepare said compound in accordance with the synthesismethod described in above-depicted Scheme 2 and Scheme 3, using as thestarting material for said method the compound prepared as described inbelow-recited Example 20, and represented by the formula:

The preferred compound depicted in the first formula above may beprepared in accordance with the synthesis methods described inabove-depicted Scheme 1, Scheme 2, and Scheme 3, and as further detailedin the below-recited Examples. Another, preferred, method of preparingsaid compound may also be employed, and is represented in the followingsynthesis scheme:

SCHEME 5

Scheme 5, illustrated below, is a more generalized representation of theabove-mentioned preferred method of preparing said above-describedpreferred compound of the present invention.

As illustrated, the starting material XXVIII is reacted with a hydrazineXXIX and the in situ product XXX is heated without separation to yieldan indazole XXXI, which is in turn reacted with dicyanocyclohexane XXXIIto yield the cyano- analog of said above-described preferred compound,XXXIII.

In step 1 of Scheme 5, the compound of formula XXVIII is treated with ahydrazine derivative of formula XXIX and an acid, preferably ammoniumacetate, in a solvent such as heptane, tetrahydrofuran, xylenes,toluene, or mesitylene, or a mixture of two or more of the foregoingsolvents, preferably toluene, to provide the compound of formula XXX. Ingeneral, the compound of formula XXX need not be separated or isolatedfrom the reaction mixture.

In step 2 of Scheme 5, the reaction mixture containing the compound offormula XXX is heated at a temperature between about 75° C. and about200° C., preferably between about 90° and 120° C., for a period of about2 hours to 48 hours, preferably 12 hours, to provide the compound offormula XXXI.

Alternatively, the process of step 1 of Scheme 5 may be accomplishedusing a salt of the hydrazine derivative, such as the hydrochloride,hydrobromide, mesylate, tosylate, or oxalate salt of said compound,preferably the mesylate salt, which is reacted with a base, such assodium or potassium acetate, in a solvent such as heptane,tetrahydrofuran, xylenes, toluene, or mesitylene, or a mixture of two ormore of the foregoing solvents, preferably toluene.

In step 3 of Scheme 5, the compound of formula XXXI is treated with thecompound of formula XXXII in the presence of a base such as lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, lithium diisopropylamide, or lithium2,2,6,6-tetramethylpiperidine, preferably potassiumbis(trimethylsilyl)amide, in a solvent such as tetrahydrofuran, toluene,or xylenes, preferably toluene, at a temperature between about 25° C.and about 125° C., preferably about 100° C., for a period 1 hour to 15hours, preferably 5 hours, to provide compound of formula XXXIII.

In step 4 of Scheme 5, the compound of formula XXXIII is treated with anacid such as hydrochloric acid, hydrobromic acid, sulfuric acid,p-toluenesulfonic acid, methanesulfonic acid, or trifluoromthanesulfonicacid, preferably hydrochloric acid, in a solvent of the formula XXXIV,i.e., R¹⁴—OH wherein R¹⁴ is as defined herein, e.g., C₁-C₆ alkyl, suchas methanol, ethanol, propanol, isopropanol, preferably ethanol, at atemperature between 0° C. and 50° C., preferably ambient temperature(20-25° C.) for a period of 1 hour to 48 hours, preferably 14 hours, toprovide a compound of formula XXXV. In general, the compound of formulaXXXV need not to be separated or isolated from the reaction mixture.

In step 5 of Scheme 5, the compound of formula XXXV is treated withwater in a solvent such as toluene, ethyl acetate, diisopropyl ether,methyl tert-butyl ether, or dichloromethane, preferably toluene, at atemperature between about 0° C. and 50° C., preferably ambienttemperature (20-25° C.) for a period of 1 hour to 24 hours, preferably 8hours, to provide a compound of formula XXXVI.

A particular version of the synthesis of Scheme 5 above carried out withreactants suitable for obtaining the preferred cyclohexanecarboxylicacid compound of the present invention, is illustrated below in Scheme6:

Scheme 7 set out below illustrates a procedure to facilitate thehandling and purification of the indazole intermediate of formula XXXIwhich is described above in reference to Scheme 5. In step 1 of Scheme7, the indazole of formula XXXI is treated with an acid, such ashydrobromic, hydrochloric, or sulfuric acid, preferably hydrobromicacid, in a solvent such as toluene, xylenes, acetic acid, or ethylacetate, preferably toluene, at a temperature ranging from 0° C. toambient temperature (20-25° C.), preferably ambient temperature, to forma salt of the compound of formula XXXVIII, wherein HX indicates the acidused to prepare the salt and X is the anion of said acid. The salt maybe separated and purified according to methods familiar to those skilledin the art. In step 2 of Scheme 7, the salt is converted back to thefree base. In this step, the salt of the compound of formula XXXVIII istreated with an aqueous base, such as sodium hydroxide, potassiumhydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, orpotassium bicarbonate, preferably sodium hydroxide, in a solvent such ashexane, toluene, dichloromethane, diisopropyl ether, methyl tert-butylether, or ethyl acetate, preferably toluene, at a temperature rangingfrom 0° C. to ambient temperature (20-25° C.), preferably ambienttemperature, for a period of 5 minutes to 1 hour, preferably 20 minutes,to provide the compound of formula XXXI.

The compounds of the formulas XXVIII-XXXVIII may have asymmetric carbonatoms and therefore exist in different enantiomeric forms.Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, for example, bychromatography or fractional crystallization. Enantiomers may beseparated by converting the enantiomeric mixtures into a diastereomericmixture by reaction with an appropriate optically active compound, e.g.,alcohol, separating the diastereomers and converting, e.g., hydrolyzing,the individual diastereomers to the corresponding pure enantiomers. Theuse of all such isomers, including diastereomer mixtures and pureenantiomers, are considered to be part of the present invention.

Further details concerning the above-identified synthesis methods whichare preferred for preparing the above-recited preferred compound of thepresent invention may be found in copending U.S. Ser. No. (AttorneyDocket No. PC10004), filed Nov. 3, 1997, which is incorporated herein byreference in its entirely.

Pharmaceutically acceptable acid addition salts of the compounds of thisinvention include, but are not limited to, those formed with HCl, HBr,HNO₃, H₂SO₄, H₃PO₄, CH₃SO₃H, p-CH₃C₆H₄SO₃H, CH₃CO₂H, gluconic acid,tartaric acid, maleic acid and succinic acid. Pharmaceuticallyacceptable cationic salts of the compounds of this invention of formulaI wherein, for example, R³ is CO₂R⁹, and R⁹ is hydrogen, include, butare not limited to, those of sodium, potassium, calcium, magnesium,ammonium, N,N′-dibenzylethylenediamine, N-methylglucamine (meglumine),ethanolamine, tromethamine, and diethanolamine.

For administration to humans in the curative or prophylactic treatmentof inflammatory diseases, oral dosages of a compound of formula I or apharmaceutically acceptable salt thereof (the active compounds) aregenerally in the range of 0.1-1000 mg daily for an average adult patient(70 kg). Individual tablets or capsules should generally contain from0.1 to 100 mg of active compound, in a suitable pharmaceuticallyacceptable vehicle or carrier. Dosages for intravenous administrationare typically within the range of 0.1 to 10 mg per single dose asrequired. For intranasal or inhaler administration, the dosage isgenerally formulated as a 0.1 to 1% (w/v) solution. In practice thephysician will determine the actual dosage which will be most suitablefor an individual patient and it will vary with the age, weight andresponse of the particular patient. The above dosages are exemplary ofthe average case but there can, of course, be individual instances wherehigher or lower dosage ranges are merited, and all such dosages arewithin the scope of this invention.

For administration to humans for the inhibition of TNF, a variety ofconventional routes may be used including orally, parenterally,topically, and rectally (suppositories). In general, the active compoundwill be administered orally or parenterally at dosages between about 0.1and 25 mg/kg body weight of the subject to be treated per day,preferably from about 0.3 to 5 mg/kg. However, some variation in dosagewill necessarily occur depending on the condition of the subject beingtreated. The person responsible for administration will, in any event,determine the appropriate dose for the individual subject.

For human use, the active compounds of the present invention can beadministered alone, but will generally be administered in an admixturewith a pharmaceutical diluent or carrier selected with regard to theintended route of administration and standard pharmaceutical practice.For example, they may be administered orally in the form of tabletscontaining such excipients as starch or lactose, or in capsules eitheralone or in admixture with excipients, or in the form of elixirs orsuspensions containing flavoring or coloring agents. They may beinjected parenterally; for example, intravenously, intramuscularly orsubcutaneously. For parenteral administration, they are best used in theform of a sterile aqueous solution which may contain other substance;for example, enough salts or glucose to make the solution isotonic.

Additionally, the active compounds may be administered topically whentreating inflammatory conditions of the skin and this may be done by wayof creams, jellies, gels, pastes, and ointments, in accordance withstandard pharmaceutical practice.

The active compounds may also be administered to a mammal other than ahuman. The dosage to be administered to a mammal will depend on theanimal species and the disease or disorder being treated. The activecompounds may be administered to animals in the form of a capsule,bolus, tablet or liquid drench. The active compounds may also beadministered to animals by injection or as an implant. Such formulationsare prepared in a conventional manner in accordance with standardveterinary practice. As an alternative the compounds may be administeredwith the animal feedstuff and for this purpose a concentrated feedadditive or premix may be prepared for mixing with the normal animalfeed.

The ability of the compounds of formula I or the pharmaceuticallyacceptable salts thereof to inhibit PDE IV may be determined by thefollowing assay.

Thirty to forty grams of human lung tissue is placed in 50 ml of pH 7.4Tris/phenylmethylsulfonyl fluoride (PMSF)/sucrose buffer and homogenizedusing a Tekmar Tissumizer® (Tekmar Co., 7143 Kemper Road, Cincinnati,Ohio 45249) at full speed for 30 seconds. The homogenate is centrifugedat 48,000×g for 70 minutes at 4° C. The supernatant is filtered twicethrough a 0.22 mm filter and applied to a Mono-Q FPLC column (PharmaciaLKB Biotechnology, 800 Centennial Avenue, Piscataway, N.J. 08854)pre-equilibrated with pH 7.4 Tris/PMSF Buffer. A flow rate of 1ml/minute is used to apply the sample to the column, followed by a 2ml/minute flow rate for subsequent washing and elution. Sample is elutedusing an increasing, step-wise NaCl gradient in the pH 7.4 Tris/PMSFbuffer. Eight ml fractions are collected. Fractions are assayed forspecific PDE_(IV) activity determined by [³H]cAMP hydrolysis and theability of a known PDE_(IV) inhibitor (e.g. rolipram) to inhibit thathydrolysis. Appropriate fractions are pooled, diluted with ethyleneglycol (2 ml ethylene glycol/5 ml of enzyme prep) and stored at −20° C.until use.

Compounds are dissolved in dimethylsulfoxide (DMSO) at a concentrationof 10 mM and diluted 1:25 in water (400 mM compound, 4% DMSO). Furtherserial dilutions are made in 4% DMSO to achieve desired concentrations.The final DMSO concentration in the assay tube is 1%. In duplicate thefollowing are added, in order, to a 12×75 mm glass tube (allconcentrations are given as the final concentrations in the assay tube).

i) 25 ml compound or DMSO (1%, for control and blank)

ii) 25 ml pH 7.5 Tris buffer

iii) [³H]cAMP (1 mM)

iv) 25 ml PDE IV enzyme (for blank, enzyme is preincubated in boilingwater for 5 minutes)

The reaction tubes are shaken and placed in a water bath (37° C.) for 20minutes, at which time the reaction is stopped by placing the tubes in aboiling water bath for 4 minutes. Washing buffer (0.5 ml, 0.1 M4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid (HEPES)/0.1M naci,pH 8.5) is added to each tube on an ice bath. The contents of each tubeare applied to an AFF-Gel 601 column (Biorad Laboratories, P.O. Box1229, 85A Marcus Drive, Melvile, N.Y. 11747) (boronate affinity gel, 1ml bed volume) previously equilibrated with washing buffer. [³H]CAMP iswashed with 2×6 ml washing buffer, and [³H]5′AMP is then eluted with 4ml of 0.25M acetic acid. After vortexing, 1 ml of the elution is addedto 3 ml scintillation fluid in a suitable vial, vortexed and counted for[³H].

% inhibition=1−average cpm (test compound−average cmp (blank)

average cpm (control)−average cpm (blank)

IC₅₀ is defined as that concentration of compound which inhibits 50% ofspecific hydrolysis of [³H]cAMP to [³H]5′AMP.

The ability of the compounds I or the pharmaceutically acceptable saltsthereof to inhibit the production TNF and, consequently, demonstratetheir effectiveness for treating disease involving the production of TNFis shown by the following in vitro assay:

Peripheral blood (100 mls) from human volunteers is collected inethylenediaminetetraacetic acid (EDTA). Mononuclear cells are isolatedby FICOLL/Hypaque and washed three times in incomplete HBSS. Cells areresuspended in a final concentration of 1×10⁶ cells per ml in pre-warmedRPMI (containing 5% FCS, glutamine, pen/step and nystatin). Monocytesare plated as 1×10⁶ cells in 1.0 ml in 24-well plates. The cells areincubated at 37° C. (5% carbon dioxide) and allowed to adhere to theplates for 2 hours, after which time non-adherent cells are removed bygentle washing. Test compounds (10 ml) are then added to the cells at3-4 concentrations each and incubated for 1 hour. LPS (10 ml) is addedto appropriate wells. Plates are incubated overnight (18 hrs) at 37° C.At the end of the incubation period TNF was analyzed by a sandwich ELISA(R&D Quantikine Kit). IC₅₀ determinations are made for each compoundbased on linear regression analysis.

The following Examples further illustrate the invention. In thefollowing examples, “DMF” means dimethylformamide, “THF” meanstetrahydrofuran, “DMSO” means dimethyl sulfoxide, and “DMAP” means4-dimethylaminopyridine.

EXAMPLE 1

A. 3-Nitro-4-propyl-benzoic acid

9.44 g (57.5 mmol, 1.0 equiv.) of 4-propylbenzoic acid were partiallydissolved in 50 mL conc. H₂SO₄ and chilled in an ice bath. A solution of4.7 mL (74.7 mmol, 1.3 equiv) conc. HNO₃ in 10 mL conc. H₂SO₄ was addeddropwise over 1-2 min. After stirring 1 hour at 0° C., the reactionmixture was poured into a 1 L beaker half full with ice. After stirring10 minutes, the white solid which formed was filtered, washed 1×H₂O, anddried to give 12.01 g (100%) of the title compound: mp 106-109° C.; IR(KBr) 3200-3400, 2966, 2875, 2667, 2554, 1706, 1618, 1537, 1299, 921cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) d 0.90 (t, 3H, J=7.4 Hz), 1.59 (m, 2H),2.82 (m, 2H), 7.63 (d, 1H, J=8.0 Hz), 8.12 (dd, 1H, J=1.7, 8.0 Hz), 8.33(d, 1H, J=1.7 Hz); ¹³C NMR (75.5 MHz, DMSO-d₆) d 14.2, 23.7, 34.2,125.4, 130.5, 132.9, 133.6, 141.4, 149.5, 165.9; Anal. calcd forC₁₀H₁₁NO₄.¼H₂O: C, 56.20; H, 5.42; N, 6.55. Found: C, 56.12; H, 5.31; N,6.81.

B. 3-Amino-4-propyl-benzoic acid

A mixture of 11.96 g (57.2 mmol) 3-nitro-4-propyl-benzoic acid and 1.5 g10% Pd/C, 50% water wet, in 250 mL CH₃OH was placed on a Parrhydrogenation apparatus and shaken under 25 psi H₂ at ambienttemperature. After 1 hour, the reaction mixture was filtered throughcelite, and the filtrate concentrated and dried to give 9.80 g (96%) ofa pale yellow crystalline solid: mp 139.5-142.5° C.; IR (Kbr) 3200-2400,3369, 3298, 2969, 2874, 2588, 1690, 1426, 916, 864 cm⁻¹; ¹H NMR (300Mhz, DMSO-d₆) d 0.90 (t, 3H, J=7.2 Hz), 1.52 (m, 2H), 2.42 (m, 2H), 5.08(brs, 2H), 6.96 (d, 1H, J=7.8 Hz), 7.05 (dd, 1H, J=1.7, 7.8 Hz), 7.20(d, 1H, J=1.7 Hz); MS (Cl, NH₃) m/z 180 (M+H⁺, base); Anal. calcd forC₁₀H₁₃NO₂.⅓H₂O: C, 64:85; N, 7.89; N, 7.56. Found: C, 64.69; H, 7.49; N,7.86.

C. 3-Carboxy-6-propyl-benzenediazo t-butyl sulfide

A mixture of 8.80 g (49.1 mmol, 1.0 equiv) 3-amino-4-propyl-benzoic acidand 2.34 g (22.1 mmol, 0.45 equiv) sodium carbonate in 55 mL H₂O washeated gently with a heat gun until mostly dissolved. The reactionmixture was chilled in an ice bath, and a solution of 3.73 g (54.0 mmol,1.0 equiv.) sodium nitrite in 27 mL H₂O was added dropwise. After 15min., the reaction mixture was transferred to a dropping funnel andadded over 10 minutes to a beaker containing 55 g of crushed ice and10.6 mL concentrated HCl. After stirring 10 min., the contents of thebeaker were transferred to a dropping funnel and added over 5 minutes toa room temperature solution of 5.31 mL (47.1 mmol, 0.96 equiv) t-butylthiol in 130 mL ethanol. The pH was adjusted to 4-5 by addition ofsaturated aqueous Na₂CO₃ solution, and the reaction mixture was allowedto stir 1 hour at ambient temperature. 200 mL brine were added, and themixture was filtered. The solid was washed 1×H₂O and dried overnight togive 12.25 g (89%) of a brown/rust colored powder (caution−stench): mp102° C. (dec); IR (KBr) 3200-2400, 2962, 2872, 2550, 1678, 1484, 1428,1298, 1171 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) d 0.84 (t, 3H, J=7.3 Hz),1.48 (m, 2H), 1.55 (s, 9H), 2.42 (m, 2H), 7.29 (d, 1H, J=1.6 Hz), 7.50(d, 1H, J=8.0 Hz), 7.86 (dd, 1H, J=1.7, 7.9 Hz), 13.18 (br s, 1H); MS(thermospray, NH₄OAc) m/z 281 (M+H+, base); Anal. calcd for C₁₄H₂₀N₂O₂S:C, 59.96; H, 7.19; N, 9.99. Found: C, 59.71; H, 7.32; N, 10.02.

D. 3-Ethyl-1H-indazole-6-carboxylic acid

A solution of 12.0 g (42.8 mmol, 1.0 equiv)3-carboxy-6-propyl-benzenediazo t-butyl sulfide in 150 mL DMSO was addeddropwise over 15 min. to a room temperature solution of 44.6 g (398mmol, 9.3 equiv) potassium t-butoxide in 200 mL DMSO. After stirring 2hours at ambient temperature, the reaction mixture was poured into 1.5 Lof 0° C. 1N HCl, stirred 5 min., then extracted 2×350 mL ethyl acetate.The ethyl acetate extracts (caution—stench) were combined, washed 2×250mL H₂O, and dried over MgSO₄. Filtration, concentration of filtrate anddrying gave a tan solid, which was triturated with 1 L of 1:3Et₂O/Hexanes and dried to give 7.08 g (87%) of a tan crystalline powder:mp 248-251° C.; IR (KBr) 3301, 3300-2400, 2973, 2504, 1702, 1455, 1401,1219 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆) d 1.31 (t, 3H, J=7.6 Hz), 2.94 (q,2H, J=7.6 Hz), 7.63 (dd, 1H, J=1.1, 8.4 Hz), 7.81 (d, 1H, J=8.4 Hz),8.06 (d, 1H, J=1.1 Hz) 12.95 (br s, 1H); MS (Cl, NH₃) m/z 191 (M+H+,base); Anal. calcd for C₁₀H₁₀N₂O₂: C, 63.14; H, 5.30; N, 14.73. Found:C, 62.66; H, 5.42; N. 14.80.

E. 3-Ethyl-1H-indazole-6-carboxylic acid methyl ester

8.78 g (45.8 mmol, 1.1 equiv)1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were addedin one portion to a room temperature solution of 7.92 g (41.6 mmol, 1.0equiv) 3-ethyl-1H-indazole-6-carboxylic acid, 16.9 mL (416 mmol, 10equiv) methanol and 5.59 g (45.8 mmol, 1.1 equiv) DMAP in 250 mL CH₂Cl₂.After 18 hours at room temperature, the reaction mixture wasconcentrated to 150 mL, diluted with 500 mL ethyl acetate, washed 2×100mL 1N HCl, 1×100 mL H₂O, 1×100 mL brine, and dried over Na₂SO₄.Filtration, concentration of filtrate and drying gave 7.8 g of a brownsolid, which was purified on a silica gel column (30% to 50% ethylacetate/hexanes gradient) to give 6.41 g (75%) of a tan solid: mp107-108° C.; IR (KBr) 3100-2950, 1723, 1222 cm⁻¹; ¹H NMR (300 MHz,CDCl₃) d 8.19 (m, 1H), 7.7-7.8 (m, 2H), 3.96 (s, 3H), 3.05 (q, 2H, J=7.7Hz), 1.43 (t, 3H, 7.7 Hz); MS (Cl, NH₃) m/z 205 (M+H⁺, base); Anal.calcd for C₁₁H₁₂N₂O₂: C, 64.70; H, 5.92; N, 13.72. Found: C, 64.88; H,6.01; N, 13.96.

F. 1-Cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid methyl ester

1.17 g (29.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, wasadded in one portion to a room temperature solution of 5.7 g (27.9 mmol,1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid methyl ester in 125 mLanhydrous DMF. After 20 minutes, 3.89 mL (36.6 mmol, 1.3 equiv)cyclopentyl bromide were added dropwise, and the reaction was mixtureallowed to stir overnight at room temperature. The mixture was thenpoured into 1 L H₂O and extracted 3×450 mL ethyl acetate. The organicextracts were combined, washed 3×400 mL H₂O, 1×200 mL brine, and driedover Na₂SO₄. Filtration, concentration of filtrate and drying gave anamber oil, which was purified on a silica gel column (10% ethylacetate/hexanes, gravity) to give 5.48 g (72%) of a clear oil: ¹H NMR(300 MHz, CDCl₃) d 8.16 (d, 1H, J=1.0 Hz), 7.7 (m, 2H), 5.00 (quintet,1H, J=7.5 Hz), 3.97 (s, 3H), 3.01 (q, 2H, J=7.6 Hz), 2.2 (m, 4H), 2.0(m, 2H), 1.8 (m, 2H), 1.39 (t, 3H, J=7.6 Hz); HRMS calcd for C₁₆H₂₀N₂O₂;272.1526. Found: 272.15078.

G. (1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-methanol

7 mL (7.0 mmol, 1.0 equiv) lithium aluminum hydride, 1.0 M solution inTHF, were added to a 0° C. solution of 1.02 g (7.05 mmol, 1.0 equiv)1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid methyl ester in 50mL anhydrous THF. After 20 minutes, 1 mL methanol was added cautiously,then the reaction mixture was poured into 500 mL of 5% H₂SO₄ andextracted 3×50 mL ethyl acetate. The organic extracts were combined,washed 2×40 mL H₂O, 1×40 mL brine, and dried over Na₂SO₄. Filtration,concentration of filtrate, and drying gave 1.58 g of a clear oil, whichwas purified on a silica gel column to give 1.53 g (89%) clear oil: IR(CHCl₃) 3606, 3411, 3009, 2972, 2875, 1621, 1490 cm⁻¹; ¹H NMR (300 Mhz,CDCl₃) d 7.65 (d, 1H, J=8.0 Hz), 7.42 (s, 1H), 7.06 (dd, 1H, J=1.0, 8.2Hz), 4.92 (quintet, 1H, J=7.7 Hz), 4.84 (s, 2H), 2.98 (q, 2H, J=7.6 Hz),2.2 (m, 4H), 2.0 (m, 2H), 1.7 (m, 3H), 1.38 (t, 3H, J=7.6 Hz); MS(thermospray, NH₄OAc) m/z 245 (M+H⁺, base); HRMS calcd for C₁₅H₂₀N₂O+H:245.1654. Found: 245.1675.

H. 1-Cyclopentyl-3-ethyl-1H-indazole-6-carbaldehyde

0.06 mg (0.301 mmol, 0.05 equiv) tetrapropylammonium perruthenate (VII)were added to a room temperature suspension of 1.47 g (6.02 mmol, 1.0equiv) (1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-methanol, 1.06 g (9.03mmol, 1.5 equiv) N-methylmorpholine N-oxide and 3.01 g 4A molecularsieves in 12 mL anhydrous CH₂Cl₂. After 30 minutes, the reaction mixturewas filtered through a short column of silica gel (eluted with CH₂Cl₂).Fractions containing product were concentrated, and the residuechromatographed on a silica gel column (15% ethyl acetate/hexanes,flash) to give 924 mg (63%) of a pale yellow solid: mp 41° C.; IR (KBr)3053, 2966, 2872, 2819, 1695 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) d 10.13 (s,1H), 7.93 (d, 1H, J=0.9 Hz), 7.77 (d, 1H, J=8.4 Hz), 7.60 (dd, 1H,J=1.2, 8.4 Hz), 5.00 (quintet, 1H, J=7.5 Hz), 3.01 (q, 2H, J=7.6 Hz),2.2 (m, 4H), 2.0 (m, 2H), 1.7 (m, 2H), 1.39 (t, 3H, J=7.5 Hz); MS (Cl,NH₃) m/z 243 (M+H⁺, base); Anal. calcd for C₁₅H₁₈N₂O: C, 74.35; H, 7.49;N, 11.56. Found: C, 74.17; H, 7.58; N, 11.79.

EXAMPLE 2

A. 4-Bromo-2-nitro-1-propyl-benzene

125 g (628 mmol, 1.0 equiv) 1-bromo-4-propyl-benzene were added in oneportion to a 10° C. solution of 600 mL concentrated H₂SO₄ and 200 mLH₂O. With vigorous mechanical stirring, a room temperature mixture of43.2 mL (691 mmol, 1.1 equiv) conc. HNO₃ (69-71%, 16M) in 150 mL conc.H₂SO₄ and 50 mL H₂O was added dropwise over 30 minutes. The ice bath wasallowed to warm to room temperature, and the reaction stirred at roomtemperature for 68 hours. The reaction mixture was poured into a 4 Lbeaker, loosely packed full with crushed ice. After stirring 1 hour, themixture was transferred to a 4 L separatory funnel and extracted 4×800mL isopropyl ether. The organic extracts were combined, washed 3×800 mLH₂O, 1×500 mL brine, and dried over Na₂SO₄. Filtration, concentration offiltrate and drying gave 150 mL of a yellow liquid, which was purifiedby silica gel chromatography (2 columns, 3 kg silica gel each, 2% ethylacetate/hexanes) to afford 63.9 g (42%) of a yellow liquid. The desiredregioisomer is the less polar of the two, which are formed in a 1:1ratio. bp 108° C., 2.0 mm; IR (CHCl₃) 3031, 2966, 2935, 2875, 1531, 1352cm⁻¹; ¹H NMR (300 MHZ, CDCl₃) d 8.01 (d, 1H, J=2.1 Hz), 7.62 (dd, 1H,J=2.1, 8.3 Hz), 7.23 (d, 1H, J=8.3 Hz), 2.81 (m, 2H), 1.67 (m, 2H), 0.98(t, 3H, J=7.4 Hz); ¹³C NMR (75.5 MHz, CDCl₃) d 13.94, 23.74, 34.43,119.6, 127.4, 133.3, 135.7, 136.4, 149.8; GCMS (El) m/z 2451243 (M⁺.),147 (base); HRMS calcd for C₉H₁₀NO₂BR+H: 243.9973. Found: 243.9954.

B. 5-Bromo-2-propyl-phenylamine

121 g (639 mmol, 3.0 equiv) of stannous chloride (anhydrous) were addedin one portion to a room temperature solution of 51.9 g (213 mmol, 1.0equiv) 4-bromo-2-nitro-1-propyl-benzene in 1200 mL absolute ethanol and12 mL (6 equiv) H₂O. After 24 hours at room temperature, most of theethanol was removed on a rotary evaporator. The residue was poured intoa 4 L beaker, three-quarters full with crushed ice and H₂O. 150 g ofNaOH pellets were added portionwise, with stirring, until the pH=10 andmost of the tin hydroxide has dissolved. The mixture was divided inhalf, and each half extracted 2×750 mL ethyl acetate. All four ethylacetate extracts were combined, washed 1×500 mL each 1N NaOH, H₂O, andbrine, then dried over Na₂SO₄. Filtration, concentration of filtrate anddrying gave a yellow liquid, which was purified on a 1.2 kg silica gelcolumn (1:12 ethyl acetate/hexanes) to give 41.83 g (92%) of a paleyellow liquid: IR (CHCl₃) 3490, 3404, 3008, 2962, 2933, 2873, 1620, 1491cm¹; ¹H NMR (300 MHz, CDCl₃) d 6.8-6.9 (m, 3H), 3.90 br s, 2H), 2.42 (m,2H0, 1.62 (m, 2H), 0.99 (t, 3H, J=7.3 Hz); GCMS (EI) m/z 215/213 (M+.),186/184 (base); Anal. calcd for C₉H₁₂NBr: C, 50.49; H, 5.65; N, 6.54.Found: C, 50.77; H, 5.70; N, 6.50.

C. 6-Bromo-3-ethyl-1H-indazole

49.22 g (230 mmol, 1.0 equiv) 5-bromo-2-propyl-phenylamine were placedin a 3 L flask and chilled in an ice bath. A 0° C. solution of 57.5 mL(690 mmol, 3.0 equiv) conc. HCl in 165 mL H₂O was added, and theresulting solid mass which formed was ground up until a fine whitesuspension resulted. 100 mL more H₂O were added, then a solution of 15.9g (230 mmol, 1.0 equiv) sodium nitrite in 75 mL H₂O was added dropwiseover 10 min. The ice bath was removed, and the reaction allowed to stirat room temperature for 30 minutes. The reaction mixture was thenfiltered through a sintered glass funnel, precooled to 0° C. Thefiltrate was chilled in an ice bath, and with mechanical stirring, a 0°C. solution/suspension of 32.8 g (313 mmol, 1.36 equiv) ammoniumtetrafluoroborate in 110 mL H₂O was added dropwise over 10 min. Thethick white suspension which formed (aryl diazonium tetrafluoroboratesalt) was allowed to stir 1.5 hours at 0° C. The mixture was thenfiltered, and the solid washed 1×200 mL 5% aq. NH₄BF₄ (cooled to 0° C.),1×150 mL CH₃OH (cooled to 0° C.), then 1×200 mL Et₂O. Drying at highvacuum, room temperature for 1 hour gave 54.47 g (76%) of the diazoniumsalt, an off-white solid.

1500 mL of ethanol free chloroform was placed in a 3 L flask, then 34.16g (348 mmol, 2.0 equiv) potassium acetate (powdered and dried) and 2.3 g(8.7 mmol, 0.05 equiv) 18-crown-6 were added. After 10 minutes thediazonium salt was added in one portion, and the reaction mixtureallowed to stir at room temperature under nitrogen atmosphere for 18hours. The mixture was then filtered, the solid washed 2× with CHCl₃,and the filtrate concentrated to give 47 g of crude product (browncrystals). Silica gel chromatography (1.23 kg silica gel, ethylacetate/hexanes gradient 15%, 20%, 40%) gave 21.6 g (55% for secondstep, 42% overall) of tan crystals: mp 112-114° C.; IR (KBr) 3205, 3008,2969, 2925, 1616, 1340, 1037 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) d 9.86 (br s,1H), 7.61 (d, 1H, J=1.3 Hz), 7.57 (d, 1H, J=8.4 Hz), 7.24 (dd, 1H,J=1.5, 8.6 Hz), 2.99 (q, 2H, J=7.6 Hz), 1.41 (t, 3H, J=7.6 Hz); MS (Cl,NH₃) m/z 227/225 (M+H⁺, base); Anal. calcd for C₉H₉N₂Br: C, 48.02; H,4.03; N, 12.45. Found: C, 48.08; H, 3.87; N, 12.45.

D. 6-Bromo-1-cyclopentyl-3-ethyl-1H-indazole

2.46 g (61.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, wasadded in 0.5 g portions to a 10° C. solution of 13.17 g (58.5 mmol, 1.0equiv) 6-bromo-3-ethyl-1H-indazole in 500 mL anhydrous DMF. The mixturewas stirred at room temperature for 20 minutes, then a solution of 8.8mL (81.9 mmol, 1.4 equiv) cyclopentyl bromide in 10 mL anhydrous DMF wasadded dropwise. After 18 hours, the reaction mixture was poured into 2 LH₂O and extracted 2×1 L ethyl acetate. The organic extracts werecombined, washed 2×750 mL H₂O, 1×500 mL brine, and dried over Na₂SO₄.Filtration, concentration of filtrate and drying gave 20.7 g of crudeproduct, which was purified on a silica gel column (1.1 kg silica gel,3% ethyl acetate/hexanes) to give 10.6 g (62%) of an amber liquid: IR(CHCl₃)2972, 2875, 1606, 1501, 1048 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) d 7.56(d, 1H, J=1.3 Hz), 7.52 (d, 1H, J=8.7 Hz), 7.17 (dd, 1H, J=1.5, 8.5 Hz),4.83 (quintet, 1H, J=7.6 Hz), 2.96 (q, 2H, J=7.6 Hz), 2.15 (m, 4H), 2.0(m, 2H), 1.65 (m, 2H), 1.36 (t, 3H, J=7.7 Hz); MS (thermospray, NH₄OAc)m/z 295/293 (M+H⁺, base); Anal. calcd for C₁₄H₁₇N₂Br: C, 57:35; H, 5.84;N, 9.55. Found: C, 57.48; H, 5.83; N, 9.90.

E. (1-Cyclopentyl-3-ethyl-1H-indazole)-6-carbaldehyde

11.6 mL (28.4 mmol, 1.0 equiv) n-BuLi, 2.45 M in hexanes, were added toa −78° C. solution of 8.32 g (28.4 mmol, 1.0 equiv)6-bromo-1-cyclopentyl-3-ethyl-1H-indazole in 200 mL anhydrous THF. After30 min. at −78° C., 8.8 mL (114 mmol, 4.0 equiv) anhydrous DMF was addeddropwise, and the reaction mixture was allowed to stir an additional 30min. at −78° C. The mixture was warmed to room temperature over 1 hour,then 125 mL 1N HCl was added. After stirring for 10 minutes, most of theTHF was removed on a rotary evaporator. The residue was diluted with 500mL H₂O, and extracted 2×250 mL ethyl acetate. The organic extracts werecombined, washed 1×100 mL H₂O, 1×100 mL brine, and dried over Na₂SO₄.Filtration, concentration of filtrate and drying gave a yellow oil,which was purified on a silica gel column (15% ethyl acetate/hexanes,gravity) to give 4.70 g (68%) of a yellow crystalline solid: ¹H NMR (300MHz, CDCl₃) identical to the spectrum of the compound from example 8.

F. (1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-acetonitrile

4.44 mL (35.0 mmol, 1.5 equiv) trimethylsilyl chloride were addeddropwise to a room temperature suspension of 5.65 g (23.3 mmol, 1.0equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbaldehyde and 3.84 g (44.3mmol, 1.9 equiv) lithium bromide in 115 mL anhydrous acetonitrile. After15 minutes, the reaction mixture was cooled in an ice bath, and 6.84 mL(38.7 mmol, 1.66 equiv) 1,1,3,3-tetramethyldisiloxane were addeddropwise, and the reaction was allowed to warm to room temperature over2 hours. The reaction mixture was heated to reflux for 6 hours, thencooled to room temperature, diluted with 300 mL CH₂Cl₂, and filteredthrough Celite®. The filtrate was concentrated and dried at high vacuum,room temperature to give 13.08 g of a tan oily solid.

This solid was dissolved in 200 mL anhydrous DMF, 259 g (52.9 mmol, 2.27equiv) sodium cyanide were added, and the mixture stirred at roomtemperature for 2 hours. The reaction mixture was then poured into 500mL H₂O and extracted 3×200 mL ethyl acetate. The organic extracts werecombined, washed 3×200 mL H₂O, 1×200 mL brine, and dried over Na₂SO₄.Filtration, concentration of filtrate and drying gave a brown oil, whichwas purified on a silica gel column (10%-20% ethyl acetate/hexanesgradient) to give 2.98 g of impure product and 2.05 g of recovered(impure) starting material.

The recovered starting material was resubjected to the reactionconditions described above, using 50 mL 1,1,3,3-tetramethyldisiloxane,followed by 50 mL DMF and 940 mg sodium cyanide. Silica gelchromatography gave 0.62 g of impure product, which was then combinedwith the 2.98 g lot of impure product and rechromatographed (10% ethylacetate/hexanes) to give 3.27 g (55%) of a yellow oil: IR (CHCl₃) 3062,2972, 2874, 2255, 1623 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) d 7.66 (d, 1H,J=8.3 Hz), 7.39 (s, 1H), 6.97 (dd, 1H, J=1.1, 8.4 Hz), 4.90 (quintet,1H, J=7.6 Hz), 3.89 (s, 2H), 2.98 (q, 2H, J=7.6 Hz), 2.2 (m, 4H), 2.0(m, 2H), 1.7 (m, 2H), 1.37 9t, 3H, J=7.4 Hz); MS (Cl, NH₃) m/z 254(M+H⁺, base); Anal. calcd for C₁₆H₁₉N₃: C, 75.86, H, 7.56; N, 16.59.Found: C, 75.84; H, 7.94; N, 16.60.

G. 4-Cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-heptanediol aciddimethyl ester

530 mL (1.26 mmol, 0.1 equiv) triton B, 40% in methanol, was added to aroom temperature solution of 3.19 g (12.6 mmol, 1.0 equiv)(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-acetonitrile in 100 mL anhydrousacetonitrile. The reaction mixture was heated to reflux, and 11.3 mL(126 mmol, 10.0 equiv) methyl acrylate was added dropwise. After 15minutes, the reaction mixture was cooled to room temperature, andconcentrated on a rotary evaporator. The residue was diluted with 300 mLether, washed 1×50 mL 1N HCl, 1×50 mL brine, and dried over Na₂SO₄.Filtration, concentration of filtrate and drying gave a brown oil, whichwas purified on a silica gel column (20% ethyl acetate/hexanes, flash)to give 4.00 g (75%) of a yellow oil: IR (CHCl₃) 3031, 2972, 2955, 2874,2250, 1735 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) d 7.68 (d, 1H, J=8.5 Hz), 7.49(s, 1H), 6.97 (d, 1H, J=8.5 Hz); 4.93 (quintet, 1H, J=7.6 Hz), 3.58 (s,6H), 2.97 (q, 2H), J=7.7 Hz), 2.45 (m, 6H), 2.2 (m, 6H), 2.0 (m, 2H),1.8 m, 2H), 1.37 (t, 3H, J=7.7 Hz); MS (Cl, NH₃) m/z 426 (M+H⁺, base);Anal. calcd for C₂₄H₃₁N₃O₄: C, 67.74; H, 7.34; N, 9.88. Found: C, 67.76;H, 7.40; N, 10.08.

H.(±)-5-Cyano-5-(1-cyclonentyl-3-ethyl-1H-indazol-6-yl)-2-oxo-cyclohexane-carboxylicacid methyl ester

924 mg (23.1 mmol, 2.5 equiv) sodium hydride, 60% oil dispersion, wasadded in one portion to a room temperature solution of 3.93 g (9.24mmol, 1.0 equiv)4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-heptanedioic aciddimethyl ester in 100 mL anhydrous 1,2-dimethoxyethane. The reactionmixture was heated to reflux under nitrogen atmosphere for 1.5 hours,then cooled to room temperature. After 18 hours, the reaction mixturewas quenched with 50 mL H₂O, poured into 200 mL ethyl acetate, andwashed 1×100 mL 1N HCl. The aqueous layer was extracted 1×50 mL ethylacetate. The organic extracts were combined, washed 1×50 mL brine, anddried over Na₂SO₄. Filtration, concentration of filtrate and drying gavea yellow oil, which was purified on a silica gel column (10% ethylacetate/hexanes) to give 2.78 g (76%) of a white amorphous solid: IR(KRr) 2954, 2871, 2240, 1663, 1619 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) d 12.27(s, 1H), 7.70 (d, 1H, J=8.5 Hz), 7.57 (s, 1H), 7.15 (dd, 1H, J=1.6, 8.5Hz), 4.93 (quintet, 1H, J=7.6 Hz), 3.78 (s, 3H), 3.05 (m, 1H), 2.98 (q,2H, J=7.6 Hz), 2.9 (m, 1H), 2.75 (m, 1H), 2.6 (m, 1H), 2.35 (m, 2H), 2.2(m, 4H), 2.0 (m, 2H), 1.75 (m, 2H), 1.38 (t, 3H, J=7.6 Hz); MS (Cl, NH₃)m/z 394 (M+H⁺, base); Anal. calcd for C₂₃H₂₇N₃O₃: C, 70.22; H, 6.92; N,10.68. Found: C, 70.07; H, 7.01; N, 10.70.

I.1-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-oxo-cyclohexanecarbonitrile

A mixture of 2.72 g (6.91 mmol, 1.0 equiv)(±)-5-cyano-5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-2-oxo-cyclohexanecarboxylicacid methyl ester and 2.58 g (44.2 mmol, 6.4 eqiv) sodium chloride in 50mL dimethyl sulfoxide and 4 mL H₂O was heated in 140° C. oil bath undernitrogen atmosphere. After 3 hours, the reaction mixture was cooled toroom temperature and allowed to stir for 72 hours. The reaction mixturewas poured into 250 mL H₂O and extracted 2×150 mL ethyl acetate. Theorganic extracts were combined, washed 2×100 mL H₂O, 1×100 mL brine, anddried over Na₂SO₄. The crude product was purified on a silica gel column(20% ethyl acetate/hexanes) to give 1.82 g (78%) of a white crystallinesolid: mp 81-89° C.; IR (KBr) 2969, 2951, 2872, 2236, 1716 cm⁻¹; ¹H NMR(300 MHz, CDCl₃) d 7.71 (d, 1H, J=8.5 Hz), 7.58 (s, 1H), 7.16 (dd, 1H,J=1.5, 8.5 Hz), 4.93 (quintet, 1H, J=7.6 Hz), 3.0 (m, 4H), 2.7 (m, 4H),2.45 (m, 2H), NH₄OAc) m/z 336 (M+H⁺, base); Anal. calcd for C₂₁H₂₅N₃O:C, 75.20; H, 7.51; N, 12.53. Found: C, 74.06; H, 7.59; N, 12.41; HRMScalcd for C₂₁H₂₅N₃O+H: 336.20778. Found 336.2088.

EXAMPLE 3

A.1-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-[1,3]dithian-2-ylidene-cyclohexane-carbonitrile

3.94 mL (9.84 mmol, 2.09 equiv) n-BuLi, 2.5 M in hexanes, was addeddropwise to a 0° C. solution of 1.88 mL (9.89 mmol, 2.1 equiv)2-trimethylsilyl-1,3-dithiane in 80 mL anhydrous THF. After 25 minutesat 0° C., the reaction mixture was cooled to −78° C. and a solution of1.58 g (4.71 mmol, 1.0 equiv)1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-oxo-cyclohexanecarbonitrilein 40 mL anhydrous THF was added. After 1 hours at −78° C., the reactionmixture was quenched by addition of 50 mL brine, then warmed to roomtemperature, diluted with 100 mL H₂O, and extracted 1×100 mL CH₂Cl₂ and1×50 mL brine, and dried over Na₂SO₄. Filtration, concentration offiltrate and drying gave a clear oil, which was purified on a silica gelcolumn (10% ethyl acetate/hexanes) to give 1.51 g (73%) of a whiteamorphous solid: IR (KBr) 2962, 2870, 2232, 1620, 1569, 1508, 1434, 1217cm⁻¹; ¹H NMR (300 MHz, CDCl₃) d 7.67 (d, 1H, J=8.5 Hz), 7.53 (s, 1H),7.15 (dd, 1H, J=1.5, 8.6 Hz), 4.92 (quintet, 1H, J=7.6 Hz), 3.36 (m,2H), 3.0 (m, 6H), 2.42 (m, 2H), 2.34 (m, 2H), 2.2 (m, 6H), 2.0 (m, 4H),1.8 (m, 2H), 1.37 (t, 3H, J=7.5 Hz); MS (Cl, NH₃) m/z 438 (M+H⁺, base);Anal. calcd for C₂₅H₃₁N₃S₂: C, 68.60; H, 7.14; N, 9.60. Found: C, 68.26;H, 7.29; N, 9.58.

B.Trans-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid methyl ester andcis-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid methyl ester

A mixture of 1.45 g (3.31 mmol, 1.0 equiv)1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-[1,3]dithian-2-ylidene-cyclohexane-carbonitrile,3.59 g (13.2 mmol, 4.0 equiv) mercury (II) chloride and 1.48 mL (16.9mmol, 5.1 equiv) 70% perchloric acid in 60 mL methanol was heated toreflux under nitrogen atmosphere. After 2 hours, the reaction mixturewas cooled to room temperature, diluted with 250 mL CH₂Cl₂ and filteredthrough Celite®. The filtrate was washed 1×100 mL saturated aqueousNaHCO₃, 1×75 mL 10% aqueous sodium sulfite, 1×100 mL H₂O, and dried overNa₂SO₄. Filtration, concentration of filtrate and drying gave a clearoil, which was purified on a silica gel column (15% ethylacetate/hexanes) to give 340 mg (27%) of trans isomer (less polar) as awhite solid, and 794 mg (63%) of cis isomer (more polar) as a whitesolid:

data for trans isomer: mp 79-82° C.; IR (KBr) 2973, 2949, 2890, 2871,2235, 1721, 1618, 1484, 1453, 1217, 1170 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) d7.67 (d, 1H, J=8.4 Hz), 7.52 (s, 1Y), 7.14 (dd, 1H, J=1.4, 8.5 Hz), 4.93(quintet, 1H, J=7.6 Hz), 3.74 (s, 3H), 2.97 (q, 2H, J=7.6 Hz), 2.85 (m1H0, 2.3 (m, 2H), 2.2 (m, 10H), 2.0 (m, 2H), 1.75 (m, 2H), 1.37 (t, 3H,J=7.6 Hz); MS (Cl, NH₃) m/z 380 (M+H⁺, base); Anal. calcd forC₂₃H₂₉N₃O₂: C, 72.79; H, 7.70; N, 11.07. Found: C, 73.05; H, 7.80; N,11.03.

data for cis isomer: mp 112-114° C.; IR (KBr) 3065, 2952, 2868, 2234,1731, 1622, 1487, 1445, 1220, 1204 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) d 7.68(d, 1H, J=8.5 Hz), 7.55 (s, 1H), 7.14 (dd, 1H, J=1.3, 8.4 Hz), 4.93(quintet, 1H, J=7.6 Hz), 3.73 (s, 3H), 2.98 (q, 2H, J=7.6 Hz), 2.42 (m,1H), 2.36 (m, 1H), 1.9-2.3 (m, 13H), 1.8 (m, 2H), 1.37 (t, 3H, J=7.5Hz); MS (Cl, NH₃) m/z 380 (M+H⁺, base); Anal. calcd for C₂₃H₂₉N₃O₂: C,72.79; H, 7.70; N, 11.07. Found: C, 72.93; H, 7.56; N, 10.92.

EXAMPLE 4

Trans-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid

A mixture of 337 mg (0.888 mmol, 1.0 equiv)trans-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid methyl ester in 10 mL methanol, 2 mL THF and 2.7 mL (2.66 mmol, 3.0equiv) 1N NaOH was allowed to stir at room temperature. After 3 hours,the reaction mixture was concentrated on a rotary evaporator, dilutedwith 100 mL H₂O, acidified to pH 1, and extracted 2×70 mL ethyl acetate.The organic extracts were combined, washed 1×50 mL H₂O, 1×50 mL brine,and dried over Na₂SO₄. Filtration, concentration and drying gave a whitesolid, which was purified on a silica gel column (5% CH₃OH/CH₂Cl₂) togive 197 mg (61%) of a white amorphous solid: IR (KBr) 3200-2500, 3060,2963, 2871, 2245, 1729, 1702, 1621, 1453, 1219 cm⁻¹; ¹H NMR (300 MHz,DMSO-d₆) d 12.4 (br s, 1H), 7.77 (d, 1H, J=8.5 Hz), 7.69 (s, 1H), 7.20(dd, 1H, J=1.3, 8.5 Hz); 5.17 (quintet, 1H, J=7.6 Hz), 2.90 (q, 2H,J=7.6 Hz), 2.75 (m, 1H), 1.9-2.3 (m, 16H), 1.7 (m, 2H), 1.28 (t, 3H,J=7.6 Hz); MS (Cl, NH₃) m/z 366 (M+H⁺, base); Anal. calcd forC₂₂H₂₇N₃O₂: C, 72.29; H, 7.45; N, 11.50. Found: C, 71.98; H, 7.75; N,11.21.

EXAMPLE 5

Cis-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid

A mixture of 831 mg (2.19 mmol, 1.0 equiv)cis-4cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid methyl ester in 20 mL methanol, 4 mL THF and 6.6 mL (6.57 mmol, 3.0equiv) 1N NaOH was allowed to stir at room temperature. After 1.5 hours,the reaction mixture was concentrated on a rotary evaporator, dilutedwith 100 mL H₂O, acidified to pH 1, and extracted 2×70 mL ethyl acetate.The organic extracts were combined, washed 1×50 mL H₂O, 1×50 mL brine,and dried over Na₂SO₄. Filtration, concentration and drying gave 0.80 gof a white solid, which was purified on a silica gel column (5%CH₃OH/CH₂Cl₂) to give 730 mg (91%) of a white crystalline solid.Recrystallization from ethyl acetate/hexanes gave 538 mg of whitecrystals: mp 197-199° C.; IR (KBr) 3200-2600, 3061, 2961, 2948, 2939,2871, 2245, 1732, 1625, 1451, 1255, 1185, 1169 cm⁻¹; ¹H NMR (300 MHz,DMSO-d₆) d 12.35 (br s, 1H), 7.77 (d, 1H, J=8.6 Hz), 7.73 (s, 1H0, 7.27(dd, 1H, J=1.5, 8.5 Hz), 5.13 (quintet, 1H, J=7.5 Hz), 2.90 (q, 2H,J=7.6 Hz), 2.42 (m, 1H), 2.30 (m, 2H), 1.7-2.1 (m, 14H), 1.29 (t, 3H,J=7.5 Hz); MS (Cl, NH₃) m/z 366 (M+H⁺, base); Anal. calcd forC₂₂H₂₇N₃O₂: C, 72.29; H, 7.45; N, 11.50. Found: C, 72.01; H, 7.60; N,11.29.

EXAMPLE 6

A. 6-Bromo-1-cyclohex-2-enyl-3-ethyl-1H-indazole

2.12 g (52.9 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, wasadded in four portions over 10 min. to a room temperature solution of11.35 g (50.4 mmol, 1.0 equiv) 6-bromo-ethyl-1H-indazole in 300 mLanhydrous DMF. After stirring 20 min., 9.0 mL (70.6 mmol, 1.4 equiv)3-bromo-cyclohexene were added dropwise, and the reaction concentratedand dried at high vacuum, room temperature to give 7.52 g of anorange/yellow solid.

This solid was dissolved in anhydrous DMF, 1.56 g (31.8 mmol, 2.27equiv) sodium cyanide were added, and the mixture stirred at roomtemperature for 2.5 h. The reaction mixture was then poured into 400 mLH₂O and extracted 3×200 mL ethyl acetate. The organic extracts werecombined, washed 3×150 mL H₂O, 1×150 mL brine, and dried over Na₂SO₄.Filtration, concentration of filtrate and drying gave a yellow oil,which was purified on a silica gel column (5%-10% ethyl acetate/hexanesgradient) to give 1.40 g (38%) of a yellow/green oil; MS (Cl, NH₃) 268(M+H⁺, base); Anal. calcd for C₁₇H₂₁N₃: C, 76.38; H, 7.92; N, 15.72.Found C, 76.43; H, 7.53; N, 15.39.

B. 6-Bromo-1-cyclohexyl-3-ethyl-1H-indazole

A mixture of 10.22 g (33.5 mmol, 1.0 equiv)6-bromo-1-cyclohex-2-enyl-3-ethyl-1H-indazole and 1.5 g 10% Pt/C in 1 Lcyclohexane was placed on a Par® hydrogenation apparatus and shakenunder 2-5 psi H₂ at room temperature. After 1 h, the reaction mixturewas filtered through celite®, and the filtrate concentrated on a rotaryevaporator and chromatographed (5% ethyl acetate/hexanes, flash) to give9.70 g (94%) of a pale yellow oil: MS (Cl, NH₃) m/z 309/307 (M+H⁺,base); Anal. calcd for C₁₅H₁₉N₂Br: C, 58.64; H, 6.23; N, 9.12. Found: C,58.56; H, 6.29; N, 8.77.

C. 1-Cyclohexyl-3-ethyl-1H-indazole-6-carbaldehyde

This compound was prepared according to the method of example 2.E.,using 5.02 g (16.3 mmol, 1.0 equiv)6-bromo-1-cyclohexyl-3-ethyl-1H-indazole as starting material to give3.65 g (87%) of a pale yellow oil: MS (Cl, NH₃) m/z 257 (M+H⁺, base);Anal. calcd for C₁₆H₂₀N₂O: C, 74.97; H, 7.87; N, 10.93. Found: C, 75.00;H, 7.70; N, 10.74.

D. (1-(Cyclohexyl-3-ethyl-1H-indazol-6-yl)-acetonitrile

2.7 mL (21.0 mmol, 1.5 equiv) trimethylsilyl chloride were addeddropwise to a room temperature suspension of 3.58 g (14.0 mmol, 1.0equiv) 1-cyclohexyl-3-ethyl-1H-indazole-6-carbaldehyde and 2.31 g (26.6mmol, 1.9 equiv) lithium bromide in 100 mL anhydrous acetonitrile. After15 min., the reaction mixture was cooled in an ice bath, and 4.1 mL(23.2 mmol, 1.66 equiv) 1,1,3,3-tetramethyldisiloxane were addeddropwise, and the reaction was allowed to warm to room temperature over30 min. The reaction mixture was heated to reflux for 3 h, then cooledto room temperature, diluted with 300 mL CH₂Cl₂, and filtered throughCelite®. The filtrate was concentrated and dried at high vacuum, roomtemperature to give 7.52 g of an orange/yellow solid.

This solid was dissolved in 100 mL anhydrous DMF, 1.56 g (31.8 mmol,2.27 equiv) sodium cyanide were added, and the mixture stirred at roomtemperature for 2.5 h. The reaction mixture was then poured into 400 mLH₂O and extracted 3×200 mL ethyl acetate. The organic extracts werecombined, washed 3×150 mL H₂O, 1×150 mL brine, and dried over Na₂SO₄.Filtration, concentration of filtrate and drying gave a yellow oil,which was purified on a silica gel column (5%-10% ethyl acetate/hexanesgradient) to give 1.40 g (38%) of a yellow/green oil: MS (Cl, NH₃) 268(M+H⁺, base); Anal. calcd for C₁₇H₂₁N₃: C, 76.38; H, 7.92; N, 15.72.Found: C, 76.43; H, 7.53; N, 15.39.

E. 4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-heptanedioic aciddimethyl ester

This compound was prepared according to the method of example 2.G.,using 1.33 g (4.98 mmol, 1.0 equiv) of(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-acetonitrile as startingmaterial, to give 1.38 g (63%) of a yellow oil; MS (Cl, NH₃) m/z 440(M+H⁺, base); Anal. calcd for C₂₅H₃₃N₃O₄: C, 68.32; H, 7.57; N, 9.56.Found: C, 68.18; H, 7.52; N, 9.28.

F.5-Cyano-5-(1-cyclohexyl-3-ethyl-1H-indazol-t-yl)-2-oxo-cyclohexanecarboxylicacid methyl ester

This compound was prepared according to the method of example 2.H.,using 1.33 g (3.03 mmol, 1.0 equiv)4-cyano-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-heptanedioic aciddimethyl ester as starting material, to give 983 mg (80%) of a whiteamorphous solid: MS (Cl, NH₃) m/z 408 (M+H⁺, base); Anal. calcd forC₂₄H₂₉N₃O₃: C, 70.75; H, 7.18; N, 10.31. Found: C, 70.75; H, 7.33; N,10.19.

G.1-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-oxo-cyclohexanecarbonitrile

This compound was prepared according to the method of example 2.I.,using 933 mg (2.29 mmol, 1.0 equiv)5-cyano-5-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-2-oxocyclohexanecarboxylicacid methyl ester as starting material, to give 588 mg (74%) of a whiteamorphous solid: MS (Cl, NH₃) m/z 350 (M+H⁺, base); Anal. calcd forC₂₂H₂₇N₃O: C, 75.62; H, 7.79; N, 12.03. Found: C, 75.57; H, 7.90; N,12.15.

EXAMPLE 7

Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid methyl ester andtrans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid methyl ester

These compounds were prepared according to the method of example 3.B.,using 540 mg (1.20 mmol, 1.0 equiv)1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-[1,3]dithian-2-ylidene-cyclohexane-carbonitrileas starting material, to give 117 mg (25%) of trans isomer as a whiteoily solid, and 233 mg (50%) of cis isomer as a white crystalline solid:

Data for trans isomer: ¹H NMR (300 MHz, CDCl₃) d 7.68 (d, 1H, J=8.4 Hz),7.50 (d, 1H, J=0.8 Hz), 7.13 (dd, 1H, J=1.6, 8.5 Hz), 4.34 (m, 1H), 3.74(s, 3H), 2.98 (q, 2H, J+7.6 Hz), 2.85 (m, 1H), 2.35 (m, 2H), 1.9-2.2 (m,12H), 1.8 (m, 2H), 1.55 (m, 2H), 1.37 (t, 3H, J=7.6 Hz); MS (Cl, NH₃)m/z 394 (M+H⁺, base); Anal. calcd for C₂₄H₃₁N₃O₂: C, 73.25; H, 7.95; N,10.68. Fund: C, 73.07; H, 8.12; N, 10.89.

Data for cis isomer 1H NMR (300 MHz, CDCl₃) d 7.68 (d, 1H, J=8.4 Hz),7.53 (d, 1H, J=0.9 Hz), 7.14 (dd, 1H, J=1.6, 8.5 Hz), 4.34 (m, 1H), 3.74(s, 3H), 2.98 (, 2H, J-7.6 Hz), 2.43 (m, 1H), 1.9-2.3 (m, 15H), 1.8 (m,1H), 1.5 (m, 2H), 1.37 (t, 3H, J=7.6 Hz); MX (Cl, NH₃) m/z 394 (M+⁺,base); Ana. calcd for C₂₄H₃₁N₃O₂: C, 73.25; H, 7.95; N, 10.68. Found: C,73.17; H, 7.89; N, 10.43.

EXAMPLE 8

Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid

This compound was prepared according to the method of example 5, using201 mg (0.511 mmol, 1.0 equiv)cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid methyl ester as starting material, to give 178 mg (92%) of a whitecrystalline solid, which was recrystallized from ethyl acetate hexanesto give 153 mg of a white crystalline powder; mp 192-194° C.; Anal.calculated for C₂₃H₂₉N₃O₂: C, 72.79; H, 7.70; N, 11.07. Found: C, 72.25;H, 7.99; N, 10.97.

EXAMPLE 9

Cis-1-(1-cyclohexyl-3-ethyl-1H-indazole-6-yl)-4-hydroxylmethylcyclohexanecarbonitrile

To a stirred solution of the product from Example 8 (220 mg, 0.58 mmol.)in dry tetrahydrofuran (5 mL) at 0° C. was added dropwise a solution ofborane in tetrahydrofuran (1M, 1.3 mL, 1.3 mmol). The mixture wasstirred at 0° C. for one hour then quenched by the slow addition ofmethanol (1 mL). The mixture was poured into water (100 mL) andextracted with ethyl acetate (2×100 mL). The organic extracts werecombined, washed with water (1×20 mL), brine (1×20 mL) dried overmagnesium sulfate and concentrated to give an oil. A separate identicalexperiment was carried out using the product from Example 8 (100 mg,0.26 mmol.) and borane in tetrahydrofuran (1M, 0.6 mL, 0.58 mmol.). Thecrude product from both experiments were combined and chromatographed onSilica Gel eluting with 2.5% methanol in methylene chloride (v/v) togive an oil. Recrystallization from ethyl acetate/hexanes yielded 214 mgwhite solid (67%) mp 117-9° C. mass spectrum (m/e) 367 (M+1, 20), 366(M+, 100).

EXAMPLE 10

Cis-4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid amide

A mixture of the product from Example 8 (150 mg, 0.4 mmol.) thionylchloride (36 uL, 0.49 mmol) and dimethylformamide (5 mL) in drymethylene chloride (3 mL) was refluxed for four hours. The mixture wascooled to 0° C. and dry ammonia gas was bubbled with chloroform (200mL), washed with water (1×40 mL) dried over magnesium sulfate andconcentrated to give a solid. Recrystallization from ethylacetate/hexane yielded 125 mg white solid (83%) mp 180-2° C. massspectrum (m/e) (M+1, 20), 379 (M+, 100).

EXAMPLE 11

Trans-4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid amide

The title compound was prepared in a manner analogous to the synthesisprovided in Example 4. The melting point of the isolated product was140-143° C.

EXAMPLE 12

Cis-1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-(1-hydroxy-1-methyl-ethyl)cyclohexanecarbonitrile

To a stirred solution of ciscyano-4-(1-cyclohexyl-3-ethyl-1H-indazolol-6-yl)-cyclohexanecarboxylicacid methyl ester (360 mg, 0.90 mmol) in 10 mL of dry tetrahydrofuran at−40° C. under nitrogen atmosphere was added 0.7 mL (2.1 mmol) of 3.0 Mmethyl magnesium bromide. Reaction mixture was allowed to warm up toroom temperature over a period of one hour and stirred at roomtemperature for 3 hours. After this time, reaction mixture was quenchedwith excess of methanol (5.0 mL) and worked up by pouring into 100 mL ofwater and acidification with oxalic acid. Extraction with ethyl acetatefollowed by washing of ethyl acetate extract with water, brine anddrying over magnesium sulfate (MgSO₄). Removal of ethyl acetate in vacuogave crude final product which was homogenous by TLC analysis.Recrystallization from ethyl acetate/hexane gave 180 mg of pure finalproduct or a white solid, mp=58-60° C. MS m/z 394 (M+H⁺, base).

EXAMPLE 13

Cis-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile

To a stirred solution of 2.9 g (8.6 mmol)1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-oxo-cyclohexanecarbonitrile(compound 2G page 35 of PC) in 100 mL absolute methanol at 0° C. wasadded sodium borohydride 382 mg (10.8 mmol) portionwise. The mixture wasstirred at 0° C. for 30 min, then quenched with 2 mL saturated ammoniumchloride solution. The mixture was concentrated to a volume of 20 mL,poured into a mixture of 100 mL water and 100 mL saturated ammoniumchloride solution and extracted with ethyl acetate (2×200 mL). Theorganic extract was combined, washed with water (1×100 mL), brine (1×100mL), dried (MgSO₄) and concentrated to give an oil. Chromatography onsilica gel eluting with ethyl acetate/hexanes (1:1) afforded an oil.Recrystallization from ethyl acetate/hexanes yielded 1.9 g (66%)cis-1-(1-cyclopentyl-3-ethyl-1H-indazole-6-yl)-4-hydroxycyclohexanecarbonitrileas a white solid. mp 107-109° C.

Anal. Calc'd. for C₂₁H₂₇N₃O: C, 74.74; H, 8.06; N, 12.45. Found: C,74.81; H, 8.04; N, 12.43.

EXAMPLE 14

Cis-1-[3-ethyl-1(4-fluorophenyl)-1H-indazol-6-yl]-4-hydroxycyclohexanecarbonitrile

The title compound was prepared in an analogous manner to that describedin the immediately preceding example for preparation ofcis-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cyclohexanecarbonitrile,starting with 0.415 g (1.148 mmol) of1-(4-fluorophenyl-3-ethyl-1H-indazol-6-yl)-4-oxo-cyclohexanecarbonitrileto give 0.28 g (76%) of white crystalline solid. mp=132-134° C.

Anal. Calc'd. for C₂₂H₂₂N₃OF: C, 72.71; H, 6.10; N, 11.56. Found: C,72.55; H, 6.22; N, 11.40.

The1-(4-fluorophenyl-3-ethyl-1H-indazol-6-yl)-4-oxo-cyclohexanecarbonitrilestarting material was prepared from6-bromo-3-ethyl-1-(4-fluorophenyl)-1H-indazole following the chemicalsynthesis sequence outlined in Scheme 3 (intermediate X→XIX) anddescribed above in more detail.

EXAMPLE 15

Cis-1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cyclohexanecarbonitrile

The title compound was prepared in an analogous manner to that describedin a preceding example for preparation ofcis-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-cyclohexanecarbonitrile,starting with1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-oxo-cyclohexanecarbonitrile.mp=124-126° C.; MS m/z 352 (M+H⁺, base).

EXAMPLE 16

Trans-1-(1-Cyclobutyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile

The title compound was prepared in an analogous manner to that describedin a preceding example for preparation ofcis-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile,starting from1-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)-4-oxocyclohexanecarbonitrile.mp=60-65° C.; MS m/z 324 (M+H⁺, base).

EXAMPLE 17

Cis-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl-)-4-hydroxy-4-methyl-cyclohexanecarbonitrileandtrans-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-4-methyl-cyclohexanecarbonitrile

To a stirred suspension of 0.275 grams (1.115 mmol) of anhydrous CeCl₃in 10 mL of dry tetra-hydrofuran under N2 atmosphere at 0° C. was addeddropwise 0.4 mL (1.115 mmol) of 3.0 N CH₃MgCl. The reaction mixture wasstirred at 0° C. for one hour. After this time, 0.3 g (0.891 mmol) of1-(1-cyclopentyl-3-ethyl-1H-indazole-6-yl)-4-oxo-cyclohexanecarbonitriledissolved in 10 mL of anhydrous tetrahydrofuran was added dropwise andthe reaction mixture stirred at 0° C. for 1 hour. The mixture wasquenched with 5 mL of 2N HOAc. The mixture was poured onto 100 mL of H₂Oand extracted with ethyl acetate (2×100 mL). The organic extracts werecombined, washed with H₂O (1×100 mL), brine (1×200 mL) and dried overMgSO₄. Filtration, concentration and purification on a silica gel column(2% EtOAc/hexane) gave 0.15 grams of less polar product (trans isomer)as amorphous solid. MS (Cl, NH₃) m/z 353 (M+H⁺, base) and 0.045 grams ofmore polar product (cis isomer) as a white crystalline product.mp=156-158° C. MS (Cl, NH₂) m/z 352 (M+H⁺, base).

EXAMPLE 18

Cis-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl-)-cyclohexanecarboxylicacid

This compound was prepared according to the method of Example 5 using0.28 g (0.767 mmol) ofcis-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid methyl ester as a starting material to give 0.24 grams (89%) ofwhite solid, which was recrystallized from ethyl acetate/hexane to give0.15 grams of white crystalline product.mp=201-203° C.; MS (m/z) 352(M+H⁺, base).

EXAMPLE 19

Trans-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl-)-cyclohexanecarboxylicacid

This compound was prepared according to the method of Example 4 using0.13 g (0.356 mmol) oftrans-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid methyl ester as a starting material to give white solid.Purification on silica gel column using 5% methanol/95% methylenechloride gave pure product (80 mg) which was recrystallized from ethylacetate/hexane to give 43 mg of white crystalline solid; mp=157-159° C.,MS (m/z) 312, (M+H⁺, base).

EXAMPLE 20

6-Bromo-3-ethyl-1-(4-fluorophenyl)-1H-indazole

Methanesulfonic acid 5-bromo-2-propionyl-phenyl ester, prepared asdescribed in U.S. Ser. No. 09/308,954, now U.S. Pat. No. 6,011,159,filed May 8, 1997 as Attorney Docket No. PC9798, 30 grams (97.66 mmol)was combined with 4-fluorophenyl hydrazine hydrochloride (31.76 g,175.33 mmol) and sodium acetate (30 g, 364 mmol) in mesitylene (400 mL).The reaction mixture was heated to reflux in a Dean-Stark apparatus for96 hours. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The crude product was diluted with500 mL of diethyl ether and 600 mL of water. Organic layer was separatedand aqueous layer extracted with 500 mL of ethyl acetate. Combinedorganic extracts were washed with water (2×600 mL), brine (1×200 mL),dried over MgSO₄ and concentrated which gave a brown-red oil. Hexane(600 mL) was added to crude reaction product and the mixture boiled in asteam bath for a few minutes. This was followed by cooling still theheterogeneous mixture to room temperature and allowing to stand at roomtemperature for 12-14 hours. The reaction mixture was filtered,undissolved solid washed with additional hexane and filtrate whichcontained approximately 80% pure desired product concentrated in vacuoto give brown-yellow solid. Purification of this product on silica gelcolumn and eluting with 15% ethyl acetate/85% hexane gave 14.1 grams oflight brown-tan solid. Recrystallization from hexane gave light tanneedles. mp=72-73° C.; MS (APCI) m/z 319 (base).

EXAMPLE 21

4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazole-6-yl]-4-hydroxy-cyclohexanecarboxylicacid ethyl ester

This compound was prepared according to the method described in Example6 of U.S. Ser. No. 09/308,954, filed May 8, 1997 as Attorney Docket No.PC9798, starting with 3.0 grams (9.4 mmol) of6-bromo-3-ethyl-1-(4-fluoro-phenyl)-1H-indazole and 2.0 grams (11.7mmol) of 4-oxo-cyclohexanecarboxylic acid ethyl ester to give aftersilica gel flash column chromatography (using 20% ethyl acetate 80%hexane as elutant) 2.17 grams of light yellow semi-solid which was amixture of diastereoisomers. ¹H NMR (400 MHz, CDCl₃) δ 1.25-1.3 (t, 3H);1.4-1.5 (t, 3H); 1.6-1.78 (m, 2H); 1.8-2.5 (m, 7H); 2.70 (m, 1H); 3.04(m, 2H); 4.16 (m, 2H); 7.17-7.28 (m, 3H); 7.61-7.79 (m, 4H); MS, m/z324.4 (M+H⁺, base).

EXAMPLE 22

4-Cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazole-6-yl]cyclohexanecarboxylicacid ethyl ester and4-[3-ethyl-1-(4-fluoro-phenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylicacid ethyl ester

This compound was prepared according to the method described in Example7 of U.S. Ser. No. 09/308,954, filed May 8, 1997 as Attorney Docket No.PC9798, starting with 2.1 grams (5.12 mmol) of4-[3-ethyl-1-(4-fluorophenyl)-1H-indazole-6-yl]-4-hydroxy-cyclohexanecarboxylicacid ethyl ester to give after silica gel Flash 40 Biotage columnchromatography (10% EtOAc/90% hexane) 0.714 grams of product whichexisted as a mixture of diastereoisomers. MS, m/z 420 (M+H⁺, base); ¹HNMR (400 MHz, CDCl₃) δ 1.27 (t, J=7.26, 3H), 1.43 (t, J=7.68, 3H), 1.57(S, 2H), 1.85-1.98 (m, 2H); 2.02-2.19 (m, 2H); 2.18-2.40 (m, 3H); 3.04(q, J=7.67, 2H); 4.15 (q, J=7.26, 2H); 7.2-7.3 (m, 3H); 7.61 (m, 2H);7.71 (s, 1H); 7.71 (d, J=8.5, 1H). In addition to the desired product4-cyano-4-[3-ethyl-1-(4fluorophenyl)-1H-indazol-6-yl]cyclohexanecarboxylicacid ethyl ester, a major byproduct, namely4-[3-ethyl-1-(4-fluoro-phenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylicacid ethyl ester (1.16 grams) was obtained. MS m/z 393 (M+H⁺, base). ¹HNMR (400 MHz, CDCl₃) δ 1.24 (m, 3H); 1.43 (m, 3H); 1.6-2.7 (m, 7H); 3.02(m, 2H); 4.13 (m, 2H); 6.17 (br, s 1H); 7.15-7.25 (m, 4H); 7.50 (s, 1H);7.61-7.67 (m, 2H).

EXAMPLE 23

Cis-4-cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]-cyclohexanecarboxylicacid

This compound was prepared in analogous manner ascis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid, synthesis of which is described in detail in Schemes I and II ofU.S. Ser. No. 09/308,954, filed May 8, 1997 as Attorney Docket No.PC9798, starting with 0.71 grams (1.694 mmol) of4-cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]-cyclohexanecarboxylicacid ethyl ester.

mp=173-175° C.; MS m/z 392 (M+H⁺, base). Anal. Calc'd for C₂₃H₂₃O₂N₂F:C, 70.57; H, 5.66; N, 10.73. Found: C, 70.39; H, 5.61; N 10.82. ¹H NMR(400 MHz, CDCl₃) δ 1.42-1.45 (t, J=7.57, 3H); 1.91 (t, J=13.28, 2H);2.09 (m, 2H); 2.23-2.35 (m, 4H); 2.40-2.48 (m, 1H); 3.06 (q, J=7.67,2H); 7.2-7.26 (m, 2H); 7.29 (d, J=7.47, 1H); 7.60 (m, 2H); 7.71 (s, 1H);7.78 (d, J=8.5, 7H).

Alternatively,cis-4-cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazole-6-yl]cyclohexane-carboxylicacid can be prepared in analogous manner ascis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid starting with 6-bromo-3-ethyl-1-(4-fluorophenyl)-1H-indazolefollowing the synthetic steps outlined in Scheme 2, step 5, and Scheme3, steps 1-7 described further above in more detail.

EXAMPLE 24

4-(3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl)-cyclohex-3-ene-carboxylicacid

To a stirred solution of 1.13 g (2.87 mmol) of4-(3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl)-cyclohex-3-ene-carboxylicacid ethyl ester dissolved in 50 mL of methanol and 15 mL oftetrahydrofuran was added 8.62 mL (8.61 mmol) of 1N sodium hydroxide andreaction mixture heated to reflux for 3 hr. After 3 hr, the reactionmixture was concentrated on a rotary evaporator, diluted with 200 mL ofH₂O, acidified to pH 1 with 1N HCl and extracted 2×200 mL ethyl acetate.The organic extracts were combined, washed with water, brine and driedover Na₂SO₄. Filtration, concentration and drying gave crude product.Recrystallization from ethyl acetate/hexane gave 0.31 grams of whitecrystalline product. mp=214-216° C.; MS, m/z 365 (M+H⁺, base).

EXAMPLE 25

1-Cyclohexyl-3-ethyl-6-fluoro-1H-indazole

To a solution of 1-(2,4-difluoro-phenyl)-propan-1-one (21.29 g, 125.1mmol) in toluene (120 mL) was added sodium acetate (26.75 g, 326.1 mmol)and cyclohexyl/hydrazine mesylate (34.0 g, 163 mmol). The reactionmixture was heated to reflux in a Dean-Stark apparatus for 12 hours. Thereaction was cooled to room temperature and poured into 1 N hydrochloricacid (100 mL). The toluene layer was separated and washed with water (75mL) and brine (75 mL). The organic layer was dried over magnesiumsulfate, filtered, and concentrated to yield 30.07 g of1-cyclohexyl-3-ethyl-6-fluoro-1H-indazole (98% yield). ¹H NMR (400 MHz,CDCl₃) d 1.33 (t, 3, J=7.7), 1.35-1.44 (m, 2), 1.47-1.96 (m, 8), 2.93(q, 2, J=7.7), 4.14-4.22 (m, 1), 6.81 (dt, 1, J=8.9, 2.1), 6.99 (dd, 1,J=9.8, 2.1), 7.40 (ddd, 1, J=8.7, 5.2, 0.4). ¹³C NMR (100 MHz, CDCl₃) d13.97, 20.53, 25.37, 25.84, 32.32, 58.18, 94.77 (d, J=27.4), 109.11 (d,J=26.0), 119.38, 121.75 (d, J=11.5), 139.89 (d, J=13.0), 146.61, 161.95(d, J=242). IR 2968, 2934, 2856, 1624, 1507, 1174, 1125, 825 cm⁻¹.Analysis calculated for C₁₅H₁₉FN₂: C, 73.14; H, 7.77; N, 11.37. Found:C, 73.33; H, 7.90; N, 11.46.

EXAMPLE 26

1-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexane-1,4-dicarbonitrile

To a solution of 1-cyclohexyl-3-ethyl-6-fluoro-1H-indazole (1.50 g, 6.09mmol) and cylohexane-1,4-dicarbonitrile (3.27 g, 24.4 mmol) in toluene(15 mL) was added potassium bis(trimethylsilyl) amide (1.82 g, 9.12mmol). The reaction mixture was heated to 100° C. and stirred for 5hours. The reaction mixture was cooled to room temperature and pouredinto 1N HCl (15 mL). The layers were separated and the organic extractswere concentrated. The crude product was stirred in 20% EtOAc/Hexanes(15 mL) for 20 minutes and the solids were filtered (1.1 g ofcyclohexane-1,4-dicarbonitrile recovered). The filtrate was concentratedto a crude oil. For characterization purposes, the diastereoisomers wereobtained by purification by chromatography on silica gel (125 g) elutingwith 2:1 hexanes/ethylacetate (1.69 g product isolated, 77% yield).Higher Rf diastereoisomer: ¹H NMR (400 MHz, CDCl₃) d 1.37 (t, 3, J=7.7),1.24-1.78 (m, 4), 1.92-2.10 (m, 6), 2.19-2.35 (m, 8), 2.98 (q, 2,J=7.7), 3.15-3.17 (m, 1), 4.30-4.39 (m, 1), 7.19 (dd, 1, J=8.5, 1.7),7.51 (d, 1, J=0.8), 7.71 (d, 1, J=8.5). ¹³C NMR (100 MHz, CDCl₃) d14.07, 20.60, 25.34, 25.79, 25.92, 32.61, 33.36, 44.30, 57.66, 105.92,117.04, 121.00, 121.52, 121.79, 122.09, 137.33, 139.54, 146.41. IR 2934,2239, 1620, 1448, 1435, 1238, 1049, 803 cm⁻¹. Analysis calculated forC₂₅H₂₈N₄: C, 76.63; H, 7.83; N, 15.54. Found: C, 76.69; H, 7.87; N,15.65. Lower Rf diastereoisomer: ¹H NMR (400 MHz, CDCl₃) d 1.36 (t, 3,J=7.7), 1.42-1.53 (m, 2), 1.74-1.82 (m, 2), 1.89-2.08 (m, 8), 2.17-2.34(m, 6), 2.58 (tt, 1, J=12.2, 3.5), 2.97 (q, 2, J=7.7), 4.28-4.36 (m, 1),7.09 (dd, 1, J=8.5, 1.7), 7.49 (d, 1, J=1.0), 7.69 (d, 1, J=8.5). ¹³CNMR (100 MHz, CDCl₃) d 14.02, 20.57, 25.32, 25.81, 27.07, 27.27, 32.57,36.04, 43.63, 57.75, 106.05, 116.65, 121.17, 121.50, 122.13, 137.17,139.54, 146.38. IR 2935, 2231, 1620, 1447, 1211, 1061, 807 cm⁻¹.Analysis calculated for C₂₅H₂₈N₄: C, 76.63; H, 7.83; N, 15.54. Found: C,76.52; H, 7.95; N, 15.37.

EXAMPLE 27

4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid ethyl ester

To a solution of1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexane-1,4-dicarbonitrile(2.589, 7.16 mmol) in ethanol (35 mL) was bubbled hydrochloric acid gasfor 20 minutes. The reaction mixture was stirred 20 minutes after whichthe solvent was concentrated. To the crude product was added toluene (20mL) and water (20 mL) and the mixture was stirred for 8 hours. Thelayers were separated and the toluene layer was concentrated to a crudefoam. For characterization purposes, the diastereoisomers were obtainedby purification by chromatography on silica gel eluting with 4:1hexanes/ethylacetate (2.37 g product isolated, 81% yield).

What is claimed is:
 1. A compound of the formula

and pharmaceutically acceptable salts thereof, wherein: R is hydrogen,C₁-C₆ alkyl, —(CH₂)_(n)(C₃-C₇ cycloalkyl) wherein n is 0 to 2, (C₁-C₆alkoxy)C₁-C₆ alkyl, C₂-C₆ alkenyl, or —(Z′)_(b)(Z″)_(c)(C₆-C₁₀ aryl)wherein b and c are independently 0 or 1, Z′ is C₁-C₆ alkylene or C₂-C₆alkenylene, and Z″ is O, S, SO₂, or NR₉, and wherein said alkyl,alkenyl, alkoxalkyl, and aryl moieties of said R groups are optionallysubstituted by one or more substituents independently selected fromhalo, hydroxy, C₁-C₅ alkyl, C₂-C₅ alkenyl, C₁-C₅ alkoxy, C₃-C₆cycloalkoxy, trifluoromethyl, nitro, CO₂R₉, C(O)NR₉R₁₀, NR₉R₁₀ andSO₂NR₉R₁₀; R₁ is hydrogen, C₁-C₇ alkyl, C₂-C₃ alkenyl, phenyl, C₃-C₇cycloalkyl, or (C₃-C₇ cycloalkyl)C₁-C₂ alkyl, wherein said alkyl,alkenyl and phenyl R₁ groups are optionally substituted with up to 3substituents independently selected from the group consisting of methyl,ethyl, trifluoromethyl, and halo, R₂ ^(a) and R₂ ^(b) are independentlyselected from the group consisting essentially of hydrogen andhereinafter recited substituents, provided that one, but not both of R₂^(a) and R₂ ^(b) must be independently selected as hydrogen, whereinsaid substituents are selected from:

wherein the dashed lines in formulas (Ia) and (Ib) independently andoptionally represent a single or double bond, provided that in formula(Ia) both dashed lines cannot both represent double bonds at the sametime; m is 0 to 4; R₃ is H, halo, cyano, C₂-C₄ alkynyl optionally monosubstituted by phenyl; C₁-C₄ alkyl optionally substituted by one or morehalogens; —CH₂NHC(O)C(O)NH₂, cyclopropyl optionally substituted by R₁₁,R₁₇, CH₂OR₉, NR₈R₁₀, CH₂NR₉R₁₀, (CO₂R₉, C(O)N₈R₁₀, C(O)CR₁₁, C(Z)H orCH═CR₁₁R₁₁; provided that R₃ is absent when the dashed line In formula(Ia) attached to the ring carbon atom to which R₃ is attached representsa double bond; R₄ is H, R₆, C(Y)R₁₄, CO₂R₁₄, C(Y)NR₁₇R₁₄, CN,C(NR₁₇)NR₁₇R₁₄, C(NOR₉)R₁₄, C(O)NR₉NR₉C(O)R₉, C(O)NR₈NR₁₇R₁₄,C(NOR₁₄)R₉, C(NR₉)NR₁₇R₁₄, C(NR₁₄)NR₉R₁₀, C(NCN)NR₁₇R₁₄, C(NCN)S(C₁-C₄alkyl), CR₉R₁₀OR₁₄, CR₉R₁₀SR₁₄, CR₉R₁₀S(O)_(n)R₁₅ wherein n is 0 to 2,CR₈R₁₀NR₁₄R₁₇, CR₉R₁₀NR₁₇SO₂R₁₅, CR₉R₁₀NR₁₇C(Y)R₁₄, CR₉R₁₀NR₁₇CO₂R₁₅,CR₈R₁₀NR₁₇C(Y)NR₁₇R₁₄, CR₉R₁₀NR₁₇C(NCN)NR₁₇R₁₄,CR₉R₁₀NR₁₇C(CR₉NO₂)S(C₁-C₄ alkyl), CR₉R₁₀CO₂R₁₆; CR₉R₁₀C(Y)NR₁₇R₁₄,CR₉R₁₀C(NR₁₇)NR₁₇R₁₄, CR₉R₁₀CN, CR₉R₁₀C(NOR₁₀)R₁₄, CR₉R₁₀C(NOR₁₄)R₁₀,CR₈R₁₀NR₁₇C(NR₁₇)S(C₁-C₄ alkyl), CR₉R₁₀NR₁₇C(NR₁₇)NR₁₇R₁₄,CR₉R₁₀NR₁₇C(O)C(O)NR₁₇R₁₄, or CR₉R₁₀NR₁₇C(O)C(O)OR₁₄; R₅ is R₈, OR₈,CH₂OR₉, cyano, C(O)R₉, CO₂R₉, C(O)NR₉R₁₀, or NR₉R₁₀, provided that R₅ isabsent when the dashed line in formula (Ia) represents a double bond; orR₄ and R₅ are taken together to form —O; or R₅ is hydrogen and R₄ isOR₁₄, SR₁₄, S(O)_(n)R₁₆ wherein n is 0 to 2, SO₂NR₁₇R₁₄, NR₁₇R₁₄,NR₁₄C(O)R₉, NR₁₇C(Y)R₁₄, NR₁₇C(O)OR₁₅, NR₁₇C(Y)NR₁₇R₁₄, NR₁₇SO₂NR₁₇R₁₄,NR₁₇C(NCN)NR₁₇R₁₄, NR₁₇SO₂R₁₅, NR₁₇C(CR₉NO₂)NR₁₇R₁₄, NR₁₇C(NCN)S(C₁-C₄alkyl), NR₁₇C(CR₉NO₇)S(C₁-C₄ alkyl), NR₁₇C(NR₁₇)NR₁₇R₁₄,NR₁₇C(O)C(O)NR₁₇R₁₄, or NR₁₇C(O)C(O)OR₁₄; R₆ is independently selectedfrom methyl and ethyl optionally substituted by one or more halogens;R₁₁ is independently fluoro or R₁₀; R₁₂ is C₁-C₆ alkyl, C₂-C₃ alkenyl,C₃-C₇ cycloalkyl, (C₃-C₇ cycloalkyl)C₁-C₂ alkyl, C₆-C₁₀ aryl, or C₃-C₉heterocyclyl, wherein said R₁₂ groups are optionally substituted with upto 3 substituents independently selected from the group consisting ofmethyl, ethyl, trifluoromethyl, and halo; R₁₃ is hydrogen or R₁₂; R₁₄ ishydrogen or R₁₅; R₁₅ is C₁-C₆ alkyl or —(CR₉R₁₀)_(n)R₁₆ wherein n is 0to 2 and R₁₀ and said C₁-C₉ alkyl are optionally substituted by one ormore substituents independently selected from halo, nitro, cyano,NR₁₀R₁₇, C(O)R₉, OR₉, C(O)NR₁₀R₁₇, OC(O)NR₁₀N₁₇, NR₁₇C(O)NR₁₇R₁₀,NR₁₇C(O)R₁₀, NR₁₇C(O)O(C₁-C₄ alkyl), C(NR₁₇)NR₁₇R₁₀, C(NCN)NR₁₇R₁₀,C(NCN)S(C₁-C₄ alkyl), NR₁₇C(NCN)S(C₁-C₄ alkyl), NR₁₇C(NON)NR₁₇R₁₀,NR₁₇SO₂(C₁-C₄ alkyl), S(O)_(n)(C₁-C₄ alkyl) wherein n is 0 to 2,NR₁₇C(O)C(O)NR₁₇R₁₀, NR₁₇C(O)C(o)R₁₇, or C₁-C₂ alkyl optionallysubstituted with one to three flourines; R₁₆ is C₃-C₇ cycloalkyl; R₁₇ isOR₈ or R₁₀; R₁₈ is H, C(Y)R₁₄, CO₂R₁₄, C(Y)NR₁₇R₁₄, CN, C(NR₁₇)NR₁₇R₁₄,C(NOR₉)R₁₄, C(O)NR₉NR₉C(O)R₈, C(O)NR₈NR₁₇R₁₄, C(NOR₁₄)R₉, C(NR₉)NR₁₇R₁₄,C(NR₁₄)NR₉R₁₀, C(NCN)NR₁₇R₁₄, C(NCN)S(C₁-C₄ alkyl), CR₈R₁₀OR₁₄,CR₉R₁₀SR₁₄, CR₉R₁₀S(O)_(n)R₁₅ wherein n is 0 to 2, CR₉R₁₀NR₁₄R₁₇,CR₉R₁₀NR₁₇SO₂R₁₅, CR₉R₁₀NR₁₇C(Y)R₁₄, CR₉R₁₀NR₁₇CO₂R₁₅,CR₉R₁₀NR₁₇C(Y)NR₁₇R₁₄, or CR₉R₁₀NR₁₇C(NCN)NR₁₇R₁₄, orCR₉R₁₀NR₁₇C(CR₅NO₂)S(C₁-C₄ alkyl); R₁₉ is —C(O)R₁₄, —C(O)NR₉R₁₄,—S(O)₂R₁₅, or —S(O)₂NR₉R₁₄, Y is O or S; and, Z is O, NR₁₇, NCN,C(—CN)₂, CR₉CN, CR₉NO₂, CR₉CO₂R₉, CR₉C(O)NR₉R₁₀, C(—CN)CO₂(C₁-C₄ alkyl)or C(CN)C(O)NR₉R₁₀.
 2. A compound according to claim 1 wherein R iscyclohexyl, cyclopentyl, cyclobutyl, methylenecyclopropyl, isopropyl,phenyl or 4-fluoro-phenyl.
 3. A compound according to claim 1 wherein R₁is C₁-C₂ alkyl optionally substituted by up to three fluorines.
 4. Acompound according to claim 1 wherein R₁ is ethyl.
 5. A compoundaccording to claim 1 wherein R₂ is a group of formula (Ia) wherein thedashed line attached to the ring carbon atom to which R₃ is attachedrepresents a single bond.
 6. A compound according to claim 1 wherein R₃is cyano.
 7. A compound according to claim 1 wherein m is 0 and R₅ ishydrogen.
 8. A compound according to claim 1 wherein R₄ is carboxy,—CH₂OH, or —CH₂C(O)NH₂.
 9. A compound according to claim 1 wherein R₂ isa group of formula (Ia) wherein R₃ and R₅ are cis as follows:


10. A compound according to claim 1 wherein R₂ is a group of formula Iawherein the dashed line attached to the ring carbon atom to which R₃ isattached represents a single bond and R₃ and R₄ are cis.
 11. A compoundaccording to claim 1 wherein R₂ is a group of formula (Ia) wherein thedashed line attached to the ring carbon atom to which R₃ is attachedrepresents a single bond, m is 0, R₅ is hydrogen and R₄ is —OH, —CH₂OH,—C(CH₃)₂OH, —CO₂H, —CO₂CH₃, —CO₂CH₂CH₃, or —CH₂C(O)NH₂.
 12. A compoundaccording to claim 1 wherein R is cyclobutyl, cyclopentyl, cyclohexyl,or 4-fluoro-phenyl; R₁ is ethyl; R₂ is a group of formula (Ia) whereinthe dashed line attached to the ring carbon atom to which R₃ is attachedrepresents a single bond, R₃ is cyano, m is 0, R₅ is hydrogen, and R₄ is—CO₂H.
 13. A compound according to claim 1 selected from the groupconsisting of:1-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-oxocyclohexanecarbonitrile;Trans-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid methyl ester;Cis-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid methyl ester;Trans-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid;Cis-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid;1-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-oxocyclohexanecarbonitrile;Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid methyl ester;Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid methyl ester;Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid;Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid;Cis-1-(1-cyclohexyl-3-ethyl-1H-indazole-6-yl)-4-hydroxymethylcyclohexanecarbonitrile;Cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid amide;Trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid amide;Cis-1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-(1-hydroxy-1-methylethyl)cyclohexanecarbonitrile;Cis-1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;Cis-1-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]-4-hydroxycyclohexanecarbonitrile;Cis-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;Cis-1-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarbonitrile;Cis-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-4-methylcyclohexanecarbonitrile;Trans-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-hydroxy-4-methylcyclohexanecarbonitrile;Cis-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid;Trans-4-cyano-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylicacid; 6-Bromo-3-ethyl-1-(4-fluorophenyl)-1H-indazole;4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]-4-hydroxycyclohexanecarboxylicacid ethyl ester;4-Cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohexanecarboxylicacid ethyl ester;4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylicacid ethyl ester;4-Cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylicacid ethyl ester;Cis-4-Cyano-4-[3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohexanecarboxylicacid;4-[3-Ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl]cyclohex-3-enecarboxylicacid; and4-(1-Cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-hydroxycyclohexanecarboxylicacid.
 14. The compound of claim 1 wherein R is cyclohexyl, cyclopentyl,methylenecyclopropyl, isopropyl, phenyl or 4-fluoro-phenyl and R₁ isethyl.
 15. A pharmaceutical composition for the inhibition ofphosphodiesterase (PDE) type IV or the production of tumor necrosisfactor (TNT) in a mammal comprising a therapeutically-effective amountof the compound of claim 1 and a pharmaceutically acceptable carrier.16. A method for the inhibition of phosphodiesterase (PDE) type IV orthe production of tumor necrosis factor (TNF) in a mammal whichcomprises administering to said mammal a therapeutically-effectiveamount of the compound of claim
 1. 17. A pharmaceutical composition forthe prevention or treatment of asthma in a mammal, comprising atherapeutically-effective amount of the compound of claim 1 and apharmaceutically acceptable carrier.
 18. A method for treating asthma ina mammal which comprising administering to said mammal a therapeuticallyeffective amount of the compound of claim 1.